2-alkoxy-substituted dicyanopyridines and their use

ABSTRACT

The present application relates to novel 2-alkoxy-substituted dicyanopyridines, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders.

The present application relates to novel 2-alkoxy-substituteddicyanopyridines, to processes for their preparation, to their use forthe treatment and/or prophylaxis of diseases and to their use forpreparing medicaments for the treatment and/or prophylaxis of diseases,preferably for the treatment and/or prevention of cardiovasculardisorders.

Adenosine, a purine nucleoside, is present in all cells and is releasedby a large number of physiological and pathophysiological stimuli.Adenosine is formed intracellularly as an intermediate during thedegradation of adenosine 5′-monophosphate (AMP) andS-adenosylhomocysteine, but it can be released from the cell, in whichcase it acts as a hormone-like substance or neurotransmitter by bindingto specific receptors.

Under normoxic conditions, the concentration of free adenosine in theextracellular space is very low. However, under ischemic or hypoxicconditions, the extracellular concentration of adenosine in the affectedorgans is increased dramatically. Thus, it is known, for example, thatadenosine inhibits platelet aggregation and increases the blood supplyto the coronary arteries. Furthermore, it acts on the blood pressure, onthe heart rate, on the release of neurotransmitters and on lymphocytedifferentiation. In adipocytes, adenosine is capable of inhibitinglipolysis, thus lowering the concentration of free fatty acids andtriglycerides in the blood.

The aim of these actions of adenosine is to increase the oxygen supplyof the affected organs and/or to reduce the metabolism of these organsin order to adjust the metabolism of the organ to the blood supply ofthe organ under ischemic or hypoxic conditions.

The action of adenosine is mediated via specific receptors. To date,subtypes A1, A2a, A2b and A3 are known. According to the invention,“adenosine-receptor-selective ligands” are substances which bindselectively to one or more subtypes of the adenosine receptors, thuseither mimicking the action of adenosine (adenosine agonists) orblocking its action (adenosine antagonists).

The actions of these adenosine receptors are mediated intracellularly bythe messenger cAMP. In the case of the binding of adenosine to the A2aor A2b receptors, the intracellular cAMP is increased via activation ofthe membrane-bound adenylate cyclase, whereas binding of adenosine tothe A1 or A3 receptors results in a decrease of the intracellular cAMPconcentration via inhibition of adenylate cyclase.

In the cardiovascular system, the main consequences of the activation ofadenosine receptors are: bradycardia, negative inotropism and protectionof the heart against ischemia (“preconditioning”) via A1 receptors,dilation of the blood vessels via A2a and A2b receptors and inhibitionof the fibroblasts and smooth-muscle-cell proliferation via A2breceptors.

In the case of A1 agonists (coupling preferably via G_(i) proteins), adecrease of the intracellular cAMP concentration is observed (preferablyafter direct prestimulation of adenylate cyclase by forskolin).Correspondingly, A2a and A2b agonists (coupling preferably via G_(s)proteins) leads to an increase and A2a and A2b antagonists to a decreaseof the cAMP concentration in the cells. In the case of A2 receptors, adirect prestimulation of adenylate cyclase by forskolin is of nobenefit.

In humans, activation of A1 receptors by specific A1 agonists leads to afrequency-dependent lowering of the heart rate, without any effect onblood pressure. Selective A1 agonists may thus be suitable inter aliafor treating angina pectoris and atrial fibrillation.

The cardioprotective action of the A1 receptors in the heart may beutilized inter alia by activating these A1 receptors with specific A1agonists for treatment and organ protection in cases of acute myocardialinfarction, acute coronary syndrome, heart failure, bypass operations,heart catheter examinations and organ transplantations.

The activation of A2b receptors by adenosine or specific A2b agonistsleads, via dilation of blood vessels, to lowering of the blood pressure.The lowering of the blood pressure is accompanied by a reflectoryincrease in heart rate. The increased heart rate can be reduced byactivation of A1 receptors using specific A1 agonists.

The combined action of selective A1/A2b agonists on the vascular systemand heart rate thus results in a systemic lowering of the blood pressurewithout relevant heart-rate increase. Dual A1/A2b agonists having such apharmacological profile could be employed, for example, for treatinghypertension in humans.

In adipocytes, the activation of A1 and A2b receptors leads to aninhibition of lipolysis. Thus, the selective or combined action of A1and A1/A2b agonists on lipid metabolism results in a lowering of freefatty acids and triglycerides. In turn, in patients suffering frommetabolic syndrome and in diabetics, reducing lipids leads to lowerinsulin resistance and improved symptoms.

In humans, the inhibition of A1 receptors by specific A1 antagonists hasa uricosuric, natriuretic and potassium-sparing diuretic effect withoutaffecting the glomerular filtration rate, thus being renoprotective.Accordingly, selective A1 antagonists can be suitable inter alia fortreating acute heart failure and chronic heart failure. Furthermore,they can be used for renoprotection in cases of nephropathy and otherrenal disorders.

The abovementioned receptor selectivity can be determined by the effectof the substances on cell lines which, after stable transfection withthe corresponding cDNA, express the receptor subtypes in question (seethe publication M. E. Olah, H. Ren, J. Ostrowski, K. A. Jacobson, G. L.Stiles, “Cloning, expression, and characterization of the unique bovineA1 adenosine receptor. Studies on the ligand binding site bysite-directed mutagenesis”, J. Biol. Chem. 267 (1992), pages10764-10770, the disclosure of which is hereby fully incorporated by wayof reference).

The effect of the substances on such cell lines can be monitored bybiochemical measurement of the intracellular messenger cAMP (see thepublication K. N. Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, B.B. Fredholm, M. J. Lohse, “Comparative pharmacology of human adenosinereceptor subtypes—characterization of stably transfected receptors inCHO cells”, Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998), pages 1-9,the disclosure of which is hereby fully incorporated by way ofreference).

The “adenosine-receptor-specific” ligands known from the prior art aremainly derivatives based on natural adenosine [S.-A. Poulsen and R. J.Quinn, “Adenosine receptors: New opportunities for future drugs”,Bioorganic and Medicinal Chemistry 6 (1998), pages 619-641]. However,most of these adenosine ligands known from the prior art have thedisadvantage that their action is not really receptor-specific, thattheir activity is less than that of natural adenosine or that they haveonly very weak activity after oral administration. Thus, they are mainlyused only for experimental purposes. Compounds of this type which arestill in clinical development are hitherto only suitable for intravenousadministration.

WO 01/25210, WO 02/070484 and WO 02/070485 disclose substituted 2-thio-and 2-oxy-3,5-dicyano-4-phenyl-6-aminopyridines as adenosine receptorligands for the treatment of cardiovascular disorders. WO 03/053441describes specific substituted2-thio-3,5-dicyano-4-phenyl-6-aminopyridines as selective ligands of theadenosine A1 receptor for the treatment of cardiovascular disorders.However, it has been found that these compounds have disadvantages withrespect to their physicochemical properties such as, for example, theirsolubility and/or formulatability, and/or with respect to their in vivoproperties, such as, for example, their pharmacokinetic behaviour, theirdose-activity relationship and/or their metabolic path.

The preparation of substituted 2-thiopyridines is described in WO98/54139. WO 99/32117 discloses substituted pyridines as acetylcholinereceptor modulators for the treatment of CNS disorders. Furthermore, WO01/62233 claims various pyridine and pyrimidine derivatives and alsotheir use as adenosine receptor modulators. Substituted3,5-dicyanopyridines as calcium-dependent potassium channel openers forthe treatment of urological disorders are disclosed in EP 1 302 463-A1.WO 03/091246 describes pyrrole-substituted pyridines and pyrimidines askinase inhibitors for the treatment of cancer, for example. WO2008/008059 describes the use of various heterocyclic compounds for thetreatment of cancer. WO 2009/015776 discloses oxazole-substituteddicyanopyridines for treating cardiovascular disorders.

It is an object of the present invention to provide novel compoundswhich act as potent and selective ligands of the adenosine A1 and/or A2breceptor and as such are suitable for the treatment and/or prevention ofdiseases, in particular for the treatment and/or prevention ofcardiovascular disorders and have an identical or improvedphysicochemical, pharmacokinetic and/or therapeutic profile compared tothe compounds known from the prior art.

The present invention provides compounds of the formula (I)

in which

-   X represents O or S,-   R¹ represents (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl,    -   where (C₆-C₁₀)-aryl and 5- to 10-membered heteroaryl may be        substituted by 1 or 2 substituents independently of one another        selected from the group consisting of halogen, nitro, cyano,        (C₁-C₆)-alkyl, trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy, amino,        mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxycarbonyl,        (C₁-C₆)-alkoxycarbonyl, aminocarbonyl,        mono-(C₁-C₆)-alkylaminocarbonyl, di-(C₁-C₆)-alkylaminocarbonyl,        (C₃-C₇)-cycloalkylaminocarbonyl, aminosulphonyl,        mono-(C₁-C₆)-alkylaminosulphonyl,        di-(C₁-C₆)-alkylaminosulphonyl, (C₁-C₆)-alkylsulphonylamino,        pyrrolidino, piperidino, morpholino, piperazino,        N′—(C₁-C₄)-alkylpiperazino, pyrrolidinocarbonyl,        piperidinocarbonyl, morpholinocarbonyl, piperazinocarbonyl,        N′—(C₁-C₄)-alkylpiperazinocarbonyl and -L-R⁵,        -   in which        -   L represents a bond, NH or O,        -   R⁵ represents phenyl or 5- or 6-membered heteroaryl,            -   where phenyl and 5- or 6-membered heteroaryl for their                part may be substituted by 1 to 3 substituents                independently of one another selected from the group                consisting of halogen, nitro, cyano, (C₁-C₆)-alkyl,                trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy,                difluoromethoxy, trifluoromethoxy, amino,                mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkyl-amino,                hydroxycarbonyl and (C₁-C₆)-alkoxycarbonyl,-   R² represents hydrogen or (C₁-C₄)-alkyl,-   R³ represents phenyl or 5- or 6-membered heteroaryl,    -   where phenyl and 5- or 6-membered heteroaryl may be substituted        by 1 to 3 substituents independently of one another selected        from the group consisting of halogen, cyano, hydroxyl,        (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₇)-cycloalkoxy,        tetrahydrofuranyloxy, pyrrolidinyloxy and —NR^(A)R^(B),        -   where (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy may be substituted by            1 to 3 substituents independently of one another selected            from the group consisting of fluorine, trifluoromethyl,            (C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₄)-alkoxy,            hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino,            aminocarbonyl, mono-(C₁-C₄)-alkylamino and            di-(C₁-C₄)-alkylamino,        -   and        -   where (C₃-C₇)-cycloalkoxy, tetrahydrofuranyloxy and            pyrrolidinyloxy may be substituted by 1 or 2 substituents            independently of one another selected from the group            consisting of (C₁-C₄)-alkyl, hydroxyl, oxo and            (C₁-C₄)-alkoxy,        -   and        -   where        -   R^(A) represents hydrogen or (C₁-C₆)-alkyl,            -   where (C₁-C₆)-alkyl for its part may be substituted by 1                to 3 fluorine substituents,            -   and            -   where (C₁-C₆)-alkyl for its part may be substituted by a                substituent selected from the group consisting of                hydroxyl and (C₁-C₄)-alkoxy,        -   R^(B) represents hydrogen, (C₁-C₆)-alkyl,            (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkylcarbonyl,            (C₁-C₄)-alkylsulphonyl or (C₃-C₇)-cycloalkylsulphonyl,            -   where (C₁-C₆)-alkyl for its part may be substituted by 1                or 2 substituents independently of one another selected                from the group consisting of fluorine, trifluoromethyl,                (C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₄)-alkoxy,                hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino,                mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,            -   and            -   where (C₃-C₇)-cycloalkyl for its part may be substituted                by 1 or 2 substituents independently of one another                selected from the group consisting of (C₁-C₄)-alkyl,                hydroxyl, oxo and (C₁-C₄)-alkoxy,        -   or        -   R^(A) and R^(B) together with the nitrogen atom to which            they are attached form a 4- to 7-membered heterocycle which            may contain a further ring heteroatom from the group            consisting of N, O and S and may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of (C₁-C₄)-alkyl, hydroxyl, oxo and            (C₁-C₄)-alkoxy,        -   or        -   where two adjacent substituents at phenyl together with the            carbon atoms to which they are attached may form a            1,3-dioxolane, 1,3-dioxane or 2,2-difluoro-1,3-dioxolane,-   R⁴ represents (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or 4- to 6-membered    heterocyclyl,    -   where (C₁-C₆)-alkyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,        (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, aminocarbonyl,        mono-(C₁-C₄)-alkylaminocarbonyl, di-(C₁-C₄)-alkylaminocarbonyl        and 5- or 6-membered heterocyclyl,        -   where (C₁-C₄)-alkoxy may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of hydroxyl and (C₁-C₄)-alkoxy        -   and        -   where 5- or 6-membered heterocyclyl may be substituted by a            substituent selected from the group consisting of oxo and            (C₁-C₄)-alkyl    -   and    -   where (C₃-C₇)-cycloalkyl and 4- to 6-membered heterocyclyl may        be substituted by 1 or 2 substituents independently of one        another selected from the group consisting of (C₁-C₄)-alkyl,        hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,        (C₁-C₄)-alkoxycarbonyl, amino, mono-(C₁-C₄)-alkylamino and        di-(C₁-C₄)-alkylamino,        and N-oxides, salts, solvates, salts of the N-oxides and        solvates of the N-oxides and salts thereof.

Compounds according to the invention are the compounds of the formula(I) and the N-oxides, salts, solvates, salts of the N-oxides andsolvates of the salts and N-oxides thereof, the compounds which areencompassed by the formula (I) of the formulae mentioned below, and thesalts, solvates and solvates of the salts thereof, and the compoundswhich are encompassed by formula (I) and are mentioned below asexemplary embodiments, and the salts, solvates and solvates of the saltsthereof, where the compounds which are encompassed by the formula (I)and are mentioned below are not already salts, solvates and solvates ofthe salts.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The invention therefore encompasses the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated from such mixtures of enantiomers and/or diastereomersin a known manner.

Where the compounds according to the invention can exist in tautomericforms, the present invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. Also included are salts which are not themselves suitable forpharmaceutical applications but can be used, for example, for theisolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulphonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases such as, by way ofexample and preferably, alkali metal salts (for example sodium andpotassium salts), alkaline earth metal salts (for example calcium andmagnesium salts) and ammonium salts derived from ammonia or organicamines having 1 to 16 carbon atoms, such as, by way of example andpreferably, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine andN-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of thecompounds according to the invention which form a complex in the solidor liquid state through coordination with solvent molecules. Hydratesare a specific form of solvates in which the coordination takes placewith water. For the purposes of the present invention, preferredsolvates are hydrates.

In addition, the present invention also encompasses prodrugs of thecompounds according to the invention. The term “prodrugs” encompassescompounds which for their part may be biologically active or inactivebut are converted (for example metabolically or hydrolytically) intocompounds according to the invention during their residence time in thebody.

For the purposes of the present invention, the substituents have thefollowing meaning, unless specified otherwise:

Alkyl is in the context of the invention a straight-chain or branchedalkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain orbranched alkyl adical having 1 to 4 carbon atoms is preferred. Thefollowing radicals may be mentioned by way of example and by way ofpreference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Cycloalkyl is in the context of the invention a monocyclic saturatedcarbocycle having 3 to 7 or 5 or 6 ring carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkylcarbonyl is in the context of the invention a straight-chain orbranched alkyl radical having 1 to 6 or 1 to 4 carbon atoms and acarbonyl group attached in position 1. The following radicals may bementioned by way of example and by way of preference: methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl and tert-butylcarbonyl.

Alkoxy is in the context of the invention a straight-chain or branchedalkoxy radical having 1 to 6 or 1 to 4 or 2 to 4 carbon atoms. Astraight-chain or branched alkoxy adical having 1 to 4 or 2 to 4 carbonatoms is preferred. The following radicals may be mentioned by way ofexample and by way of preference: methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Cycloalkoxy is in the context of the invention a monocyclic saturatedcarbocycle having 3 to 7 carbon atoms which is attached via an oxygenatom. The following radicals may be mentioned by way of example and byway of preference: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and cycloheptyloxy.

Alkoxycarbonyl is in the context of the invention a straight-chain orbranched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms and acarbonyl group attached at the oxygen. A straight-chain or branchedalkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group ispreferred. The following radicals may be mentioned by way of example andby way of preference: methoxy-carbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Monoalkylamino is in the context of the invention an amino group havinga straight-chain or branched alkyl substituent having 1 to 6 or 1 to 4carbon atoms. A straight-chain or branched monoalkylamino radical having1 to 4 carbon atoms is preferred. The following radicals may bementioned by way of example and by way of preference: methylamino,ethylamino, n-propylamino, isopropylamino, n-butylamino,tert-butylamino, n-pentylamino and n-hexylamino.

Dialkylamino is in the context of the invention an amino group havingtwo identical or different straight-chain or branched alkyl substituentshaving 1 to 6 or 1 to 4 carbon atoms each. Straight-chain or brancheddialkylamino radicals having 1 to 4 carbon atoms each are preferred. Thefollowing radicals may be mentioned by way of example and by way ofpreference: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-iso-propyl-N-n-propylamino,N,N-diisopropylamino, N-n-butyl-N-methylamino,N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino andN-n-hexyl-N-methylamino.

Cycloalkylamino is in the context of the invention an amino group havinga monocyclic saturated carbocycle having 3 to 7 carbon atoms. Thefollowing radicals may be mentioned by way of example and by way ofpreference: cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and cycloheptylamino.

Monoalkylaminocarbonyl is in the context of the invention an amino groupwhich is attached via a carbonyl group and has a straight-chain orbranched alkyl substituent having 1 to 6 or 1 to 4 carbon atoms. Amonoalkylaminocarbonyl radical having 1 to 4 carbon atoms in the alkylgroup is preferred. The following radicals may be mentioned by way ofexample and by way of preference: methylaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl,n-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl andn-hexylaminocarbonyl.

Dialkylaminocarbonyl is in the context of the invention an amino groupwhich is attached via a carbonyl group and which has two identical ordifferent straight-chain or branched alkyl substituents having 1 to 6 or1 to 4 carbon atoms each. A dialkylaminocarbonyl radical having in eachcase 1 to 4 carbon atoms per alkyl group is preferred. The followingradicals may be mentioned by way of example and by way of preference:N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-n-butyl-N-methylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl,N-n-pentyl-N-methylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

Cycloalkylaminocarbonyl is in the context of the invention an aminogroup which is attached via a carbonyl group and has a monocyclicsaturated carbocycle having 3 to 7 carbon atoms. The following radicalsmay be mentioned by way of example and by way of preference:cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,cyclopentylaminocarbonyl, cyclohexyl-aminocarbonyl andcycloheptylaminocarbonyl.

Monoalkylaminosulphonyl is in the context of the invention an aminogroup which is attached via a sulphonyl group and which has astraight-chain or branched alkyl substituent having 1 to 6 carbon atoms.The following radicals may be mentioned by way of example and by way ofpreference: methylaminosulphonyl, ethylaminosulphonyl,n-propylaminosulphonyl, isopropyl-aminosulphonyl, n-butylaminosulphonyland tert-butylaminosulphonyl.

Dialkylaminosulphonyl is in the context of the invention an amino groupwhich is attached via a sulphonyl group and which has two identical ordifferent straight-chain or branched alkyl substituents having 1 to 6carbon atoms each. The following radicals may be mentioned by way ofexample and by way of preference: N,N-dimethylaminosulphonyl,N,N-diethylaminosulphonyl, N-ethyl-N-methylaminosulphonyl,N-methyl-N-n-propylaminosulphonyl, N-n-butyl-N-methylamino-sulphonyl andN-tert-butyl-N-methylaminosulphonyl.

Alkylsulphonyl is in the context of the invention a straight-chain orbranched alkyl radical which has 1 to 4 carbon atoms and is attached viaa sulphonyl group. The following radicals may be mentioned by way ofexample and by way of preference: methylsulphonyl, ethylsulphonyl,n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl andtert-butylsulphonyl.

Cycloalkylsulphonyl is in the context of the invention a monocyclicsaturated carbocycle which has 3 to 7 carbon atoms and is attached via asulphonyl group. The following radicals may be mentioned by way ofexample and by way of preference: cyclopropylsulphonyl,cyclobutylsulphonyl, cyclopentylsulphonyl, cyclohexylsulphonyl andcycloheptylsulphonyl.

Alkylsulphonylamino is in the context of the invention an amino grouphaving a straight-chain or branched alkylsulphonyl substituent which has1 to 6 carbon atoms and which is attached via the sulphonyl group to thenitrogen atom. The following radicals may be mentioned by way of exampleand by way of preference: methylsulphonylamino, ethylsulphonylamino,n-propylsulphonylamino, isopropylsulphonylamino, n-butylsulphonylamino,tert-butylsulphonylamino, n-pentylsulphonylamino andn-hexylsulphonylamino.

Aryl is in the context of the invention an aromatic carbocycle having 6or 10 ring carbon atoms. Preferred aryl radicals are phenyl andnaphthyl.

Heterocyclyl is in the context of the invention a saturated heterocyclehaving a total of 4 to 7 ring atoms which contains one or two ringheteroatoms from the group consisting of N, O and S and is attached viaa ring carbon atom or, if appropriate, via a ring nitrogen atom. Thefollowing radicals may be mentioned by way of example: azetidinyl,pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.Azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,tetrahydropyranyl and morpholinyl are preferred.

Heteroaryl is in the context of the invention a monocyclic or optionallybicyclic aromatic heterocycle (heteroaromatic) which has a total of 5 to10 ring atoms, contains up to three identical or different ringheteroatoms from the group consisting of N, O and S and is attached viaa ring carbon atom or, if appropriate, via a ring nitrogen atom. Thefollowing radicals may be mentioned by way of example: furyl, pyrrolyl,thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl,benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl,naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrazolo[3,4-b]pyridinyl. Preference is given to monocyclic 5- or6-membered heteroaryl radicals having up to two ring heteroatoms fromthe group consisting of N, O and S, such as, for example, furyl,thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl,imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

Halogen includes in the context of the invention fluorine, chlorine,bromine and iodine. Preference is given to chlorine or fluorine.

An oxo group is in the context of the invention an oxygen atom which isattached via a double bond to a carbon atom.

When radicals in the compounds according to the invention aresubstituted, the radicals may be mono- or polysubstituted, unlessspecified otherwise. For the purposes of the present invention, themeanings of all radicals which occur more than once are independent ofone another. Preference is given to substitution by one, two or threeidentical or different substituents. Very particularly preferred issubstitution by one or two identical or different substituents.

In the context of the present invention, preference is given tocompounds of the formula (I) in which

-   X represents S,-   R¹ represents phenyl or 5- or 6-membered heteroaryl,    -   where phenyl and 5- or 6-membered heteroaryl may be substituted        by 1 or 2 substituents independently of one another selected        from the group consisting of fluorine, chlorine, cyano,        (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy, amino,        mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino, hydroxycarbonyl,        (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,        mono-(C₁-C₄)-alkylaminocarbonyl, di-(C₁-C₄)-alkylaminocarbonyl,        (C₃-C₆)-cycloalkylaminocarbonyl, (C₁-C₄)-alkylsulphonylamino,        morpholino, piperazino, N′-(C₁-C₄)-alkylpiperazino and -L-R⁵,        -   in which        -   L represents a bond or NH,        -   R⁵ represents phenyl or 5- or 6-membered heteroaryl,            -   where phenyl and 5- or 6-membered heteroaryl for their                part may be substituted by 1 or 2 substituents                independently of one another selected from the group                consisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl,                trifluoromethyl, (C₁-C₄)-alkoxy, trifluoromethoxy,                amino, hydroxycarbonyl and (C₁-C₄)-alkoxycarbonyl,-   R² represents hydrogen or methyl,-   R³ represents phenyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,    pyrazolyl, imidazolyl and pyridyl,    -   where phenyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,        pyrazolyl, imidazolyl and pyridyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, (C₁-C₆)-alkyl, hydroxyl,        (C₁-C₄)-alkoxy and —NR^(A)R^(B),        -   where (C₁-C₆)-alkyl and (C₁-C₄)-alkoxy may be substituted by            1 to 3 substituents independently of one another selected            from the group consisting of fluorine, trifluoromethyl,            hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino,            methylamino, ethylamino, N,N-dimethylamino and            N,N-diethylamino,        -   and        -   in which        -   R^(A) represents hydrogen or (C₁-C₄)-alkyl,            -   where (C₁-C₄)-alkyl for its part may be substituted by a                substituent selected from the group consisting of                hydroxyl and (C₁-C₄)-alkoxy,        -   R^(B) represents hydrogen or (C₁-C₄)-alkyl,            -   where (C₁-C₄)-alkyl for its part may be substituted by 1                or 2 substituents independently of one another selected                from the group consisting of hydroxyl, (C₁-C₄)-alkoxy                and hydroxycarbonyl,-   R⁴ represents (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or 5- or 6-membered    heterocyclyl,    -   where (C₁-C₆)-alkyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,        methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl,        ethoxycarbonyl, amino, methylamino, ethylamino,        N,N-dimethylamino, N,N-diethylamino and 5- or 6-membered        heterocyclyl,        -   where 5- or 6-membered heterocyclyl for its part may be            substituted by a substituent selected from the group            consisting of oxo and methyl,    -   and    -   where (C₄-C₆)-cycloalkyl and 5- or 6-membered heterocyclyl may        be substituted by 1 or 2 substituents independently of one        another selected from the group consisting of methyl, hydroxyl,        methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,        amino, methylamino and N,N-dimethylamino,        and salts, solvates and solvates of the salts thereof.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   X represents O or S,-   R¹ represents phenyl, thiazolyl, oxazolyl or pyridyl,    -   where phenyl and pyridyl are substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy,        hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,        methylaminocarbonyl, ethylaminocarbonyl,        N,N-dimethylaminocarbonyl and N,N-diethylaminocarbonyl,    -   and    -   where thiazolyl and oxazolyl are substituted by a -L-R⁵        substituent,        -   in which        -   L represents a bond or NH,        -   R⁵ represents phenyl,            -   where phenyl for its part may be substituted by 1 or 2                substituents independently of one another selected from                the group consisting of fluorine, chlorine, methyl,                methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and                ethoxycarbonyl,    -   and    -   where thiazolyl and oxazolyl may be substituted by substituents        selected from the group consisting of fluorine, methyl, ethyl,        methoxy, hydroxycarbonyl and methoxycarbonyl,-   R² represents hydrogen or methyl,-   R³ represents phenyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,    pyrazolyl, imidazolyl and pyridyl,    -   where phenyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,        pyrazolyl, imidazolyl and pyridyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of fluorine, (C₁-C₆)-alkyl, hydroxyl,        (C₁-C₄)-alkoxy and —NR^(A)R^(B),        -   where (C₁-C₆)-alkyl and (C₁-C₄)-alkoxy may be substituted by            1 to 3 substituents independently of one another selected            from the group consisting of fluorine, trifluoromethyl,            hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino,            methylamino, ethylamino, N,N-dimethylamino and            N,N-diethylamino,        -   and        -   in which        -   R^(A) represents hydrogen or (C₁-C₄)-alkyl,            -   where (C₁-C₄)-alkyl for its part may be substituted by a                substituent selected from the group consisting of                hydroxyl and (C₁-C₄)-alkoxy,        -   R^(B) represents hydrogen or (C₁-C₄)-alkyl,            -   where (C₁-C₄)-alkyl for its part may be substituted by 1                or 2 substituents independently of one another selected                from the group consisting of hydroxyl, (C₁-C₄)-alkoxy                and hydroxycarbonyl,-   R⁴ represents (C₁-C₆)-alkyl or (C₄-C₆)-cycloalkyl,    -   where (C₁-C₆)-alkyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,        methoxy and ethoxy,    -   and    -   where (C₄-C₆)-cycloalkyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of methyl, hydroxyl and methoxy,        and salts, solvates and solvates of the salts thereof.

In the context of the present invention, particular preference is givento compounds of the formula (I) in which

-   X represents S,-   R¹ represents phenyl, thiazolyl, oxazolyl or pyridyl,    -   where phenyl and pyridyl are substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy,        hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,        methylaminocarbonyl, ethylaminocarbonyl,        N,N-dimethylaminocarbonyl and N,N-diethylaminocarbonyl,    -   and    -   where thiazolyl and oxazolyl are substituted by a -L-R⁵        substituent,        -   in which        -   L represents a bond or NH,        -   R⁵ represents phenyl,            -   where phenyl for its part may be substituted by 1 or 2                substituents independently of one another selected from                the group consisting of fluorine, chlorine, methyl,                methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and                ethoxycarbonyl,    -   and    -   where thiazolyl and oxazolyl may be substituted by a substituent        selected from the group consisting of fluorine, methyl, ethyl,        methoxy, hydroxycarbonyl and methoxycarbonyl,-   R² represents hydrogen,-   R³ represents phenyl or thiazolyl,    -   where phenyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of (C₁-C₆)-alkyl, hydroxyl and (C₁-C₄)-alkoxy,        -   where (C₁-C₆)-alkyl and (C₂-C₄)-alkoxy may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of hydroxyl and methoxy,    -   and    -   where thiazolyl may be substituted by a (C₁-C₆)-alkyl        substituent,        -   where (C₁-C₆)-alkyl may be substituted by 1 or 2            substituents independently of one another selected from the            group consisting of hydroxyl and methoxy,-   R⁴ represents (C₁-C₄)-alkyl,    -   where alkyl may be substituted by 1 or 2 hydroxyl substituents,        and salts, solvates and solvates of the salts thereof.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   R¹ represents phenyl or pyridyl,    -   where phenyl and pyridyl are substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy,        hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,        methylaminocarbonyl, ethylaminocarbonyl,        cyclopropylaminocarbonyl, N,N-dimethylaminocarbonyl and        N,N-diethylaminocarbonyl.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   R¹ represents thiazolyl or oxazolyl,    -   where thiazolyl and oxazolyl are substituted by a -L-R⁵        substituent,        -   in which        -   L represents a bond or NH,        -   R⁵ represents phenyl,            -   where phenyl for its part may be substituted by 1 or 2                substituents independently of one another selected from                the group consisting of fluorine, chlorine, methyl,                methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl and                ethoxycarbonyl,    -   and    -   where thiazolyl and oxazolyl may be substituted by substituents        selected from the group consisting of fluorine, methyl, methoxy,        hydroxycarbonyl and methoxycarbonyl.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   R³ represents phenyl,    -   where phenyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of hydroxyl, (C₁-C₆)-alkyl and (C₁-C₄)-alkoxy,        -   where (C₁-C₆)-alkyl and (C₂-C₄)-alkoxy may be substituted by            1 or 2 substituents independently of one another selected            from the group consisting of hydroxyl and methoxy.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   R⁴ represents (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or 5- or 6-membered    heterocyclyl,    -   where (C₁-C₆)-alkyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,        methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl,        ethoxycarbonyl, amino, methylamino, ethylamino,        N,N-dimethylamino, N,N-diethylamino and 5- or 6-membered        heterocyclyl,        -   where ethoxy for its part may be substituted by a            substituent selected from the group consisting of hydroxyl            and methoxy,    -   and    -   where (C₃-C₇)-cycloalkyl and 5- or 6-membered heterocyclyl may        be substituted by 1 or 2 substituents independently of one        another selected from the group consisting of methyl, hydroxyl,        methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,        amino, methylamino and N,N-dimethylamino.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which X represents O or S.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which X represents S.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which X represents O.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which R² represents hydrogen.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which R² represents methyl.

In the context of the present invention, preference is also given tocompounds of the formula (I) in which

-   R⁴ represents (C₁-C₄)-alkyl,    -   where alkyl may be substituted by 1 or 2 hydroxyl substituents.

The present invention furthermore provides a process for preparing thecompounds of the formula (I) according to the invention, characterizedin that

-   [A] a compound of the formula (II-A)

-   -   in which X, R¹, R² and R³ each have the meanings given above,    -   is initially, using copper(II) chloride and isoamyl nitrite in a        suitable solvent, converted into a compound of the formula        (III-A)

-   -   in which X, R¹, R² and R³ each have the meanings given above,    -   and this is then reacted in an inert solvent in the presence of        a suitable base with a compound of the formula (IV)

R⁴—OH  (IV),

-   -   in which R⁴ has the meaning given above,

-   oder

-   [B] in the case that X represents S, a compound of the formula    (II-B)

-   -   in which R³ and R⁴ each have the meanings given above,    -   is reacted in an inert solvent with an alkali metal sulphide to        give a compound of the formula (III-B)

-   -   in which R³ and R⁴ each have the meanings given above,    -   and this is then reacted in an inert solvent in the presence of        a base with a compound of the formula (V)

-   -   in which R¹ and R² have the meanings given above and    -   Q represents a suitable leaving group, preferably halogen, in        particular chlorine, bromine or iodine, or represents mesylate,        tosylate or triflate,        any protective groups present are then removed and the resulting        compounds of the formula (I) are, if appropriate, converted with        the appropriate (i) solvents and/or (ii) bases or acids into        their solvates, salts and/or solvates of the salts.

In this process, any functional groups present in the compounds of theformulae (II-A) and (II-B) or in the radicals R³ and/or R⁴—such as, inparticular, amino, hydroxyl and carboxyl groups—can, if expedient orrequired, also be present in temporarily protected form. Theintroduction and removal of such protective groups takes place in thisconnection by conventional methods known to the person skilled in theart [see, for example, T. W. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, Wiley, New York, 1999; M. Bodanszky and A.Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin,1984]. If a plurality of protective groups is present, the removal may,if appropriate, take place simulataneously in a one-pot reaction or inseparate reaction steps.

The amino protective group which is preferably used istert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z). Suitable forprotecting carboxyl groups are in particular the appropriate methyl,ethyl or tert-butyl esters. A preferred protective group used for ahydroxyl function is benzyl or a silyl group such as trimethylsilyl,tert-butyldimethylsilyl or dimethylphenylsilyl. If a 1,2- or 1,3-diolgrouping is present, preference is given to using a ketal derived fromsymmetric ketones such as acetone or cyclohexanone (1,3-dioxolane or1,3-dioxane) as joint protective group.

The process described above can be illustrated in an exemplary manner byReaction Schemes 1 and 2 below:

Suitable solvents for the reaction (III-A)+(IV) are all organic solventswhich are inert under the reaction conditions. These include ketones,such as acetone and methyl ethyl ketone, acyclic and cyclic ethers, suchas diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane,tetrahydrofuran and dioxane, esters, such as ethyl acetate or butylacetate, hydrocarbons, such as benzene, toluene, xylene, hexane andcyclohexane, chlorinated hydrocarbons, such as dichloromethane,trichloromethane and chlorobenzene, or other solvents, such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N-methylpyrrolidinone (NMP), acetonitrile or pyridine. It is alsopossible to use mixtures of the solvents mentioned above. Preference isgiven to using dimethylformamide.

Suitable bases for this reaction are the customary inorganic or organicbases. These preferably include alkali metal hydrides, such as sodiumhydride, alkali metal hydroxides, such as, for example, lithiumhydroxide, sodium hydroxide or potassium hydroxide, alkali metalcarbonates, such as lithium carbonate, sodium carbonate, potassiumcarbonate or caesium carbonate, alkali metal bicarbonates, such assodium bicarbonate or potassium bicarbonate, alkali metal alkoxides,such as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, amides, such as sodiumamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amideor potassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds, such as butyllithium or phenyllithium, ororganic amines, such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and also phosphazene bases(“Schwesinger bases”), such as, for example, P2-t-Bu or P4-t-Bu.Preference is given to caesium carbonate, potassium tert-butoxide,sodium hydride and P4-tBu.

Here, the base can be employed in an amount of from 1 to 10 mol,preferably from 1 to 5 mol, in particular from 1 to 3 mol, based on 1mol of the compound of the formula (IV).

The reaction (III-A)+(IV) is generally carried out in a temperaturerange of from −78° C. to +140° C., preferably in the range from −20° C.to +100° C., in particular at from 0° C. to +60° C., if appropriate in amicrowave oven. The reaction can be carried out at atmospheric, elevatedor reduced pressure (for example in the range from 0.5 to 5 bar). Thereaction is generally carried out at atmospheric pressure.

The process step (II-A)→(III-A) is generally carried out in a molarratio of from 2 to 12 mol of copper(II) chloride and 2 to 12 mol ofisoamyl nitrite per mole of the compound of the formula (II-A).

Suitable solvents for this process step are all organic solvents whichare inert under the reaction conditions. These include acyclic andcyclic ethers, such as diethyl ether and tetrahydrofuran, esters, suchas ethyl acetate or butyl acetate, hydrocarbons, such as benzene,toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons, suchas dichloromethane, 1,2-dichloroethane and chlorobenzene, or othersolvents, such as dimethylformamide, acetonitrile or pyridine. It isalso possible to use mixtures of the solvents mentioned above. Preferredsolvents are acetonitrile and dimethylformamide.

The reaction is generally carried out in a temperature range of from−78° C. to +180° C., preferably in the range from +20° C. to +100° C.,in particular at from +20° C. to +60° C., if appropriate in a microwaveoven. The reaction can be carried out at atmospheric, elevated orreduced pressure (for example in the range from 0.5 to 5 bar). Thereaction is generally carried out at atmospheric pressure.

Suitable solvents for the reaction (III-B)+(V) are all organic solventswhich are inert under the reaction conditions. These include ketones,such as acetone and methyl ethyl ketone, acyclic and cyclic ethers, suchas diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane,tetrahydrofuran and dioxane, esters, such as ethyl acetate or butylacetate, hydrocarbons, such as benzene, toluene, xylene, hexane andcyclohexane, chlorinated hydrocarbons, such as dichloromethane,trichloromethane and chlorobenzene, or other solvents, such asdimethylformamide (DMF), dimethyl sulphoxide (DMSO),N-methylpyrrolidinone (NMP), acetonitrile or pyridine. It is alsopossible to use mixtures of the solvents mentioned above. Preference isgiven to using dimethylformamide.

Suitable bases for this reaction are the customary inorganic or organicbases. These preferably include alkali metal hydrides, such as sodiumhydride, alkali metal hydroxides, such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, alkali metal carbonates, such aslithium carbonate, sodium carbonate, potassium carbonate or caesiumcarbonate, alkali metal bicarbonates, such as sodium bicarbonate orpotassium bicarbonate, alkali metal alkoxides, such as sodium methoxideor potassium methoxide, sodium ethoxide or potassium ethoxide orpotassium tert-butoxide, amides, such as sodium amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, organometalliccompounds, such as butyllithium or phenyllithium, or organic amines,such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]-non-5-ene (DBN). Preference is given to usingsodium bicarbonate.

Here, the base is generally employed in an amount of from 1 to 1.25 mol,preferably in an equimolar amount, based on 1 mol of the compound of theformula (V).

The reaction (III-B)+(V) is generally carried out in a temperature rangeof from −20° C. to +120° C., preferably at from +20° C. to +100° C., ifappropriate in a microwave oven. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example in the range from0.5 to 5 bar). The reaction is generally carried out at atmosphericpressure.

In the reaction (II-B)→(III-B), the alkali metal sulphide used ispreferably sodium sulphide in an amount of from 1 to 10 mol, preferablyfrom 1 to 8 mol, in particular from 1 to 5 mol, per mole of the compoundof the formula (II-B).

Suitable solvents for this process step are all organic solvents whichare inert under the reaction conditions. These include alcohols, such asmethanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol,ketones, such as acetone and methyl ethyl ketone, acyclic and cyclicethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran anddioxane, esters, such as ethyl acetate or butyl acetate, hydrocarbons,such as benzene, toluene, xylene, hexane and cyclohexane, chlorinatedhydrocarbons, such as dichloromethane, 1,2-dichloroethane andchlorobenzene, or dipolar solvents, such as acetonitrile, pyridine,dimethylformamide, dimethyl sulphoxide or N-methylpyrrolidinone. Anothersuitable solvent is water. It is also possible to use mixtures of thesolvents mentioned above. The preferred solvent is dimethylformamide.

The reaction is generally carried out in a temperature range of from 0°C. to +180° C., preferably in the range from +20° C. to +120° C., inparticular at from +40° C. to +100° C., if appropriate in a microwaveoven. The reaction can be carried out at atmospheric, elevated orreduced pressure (for example in the range from 0.5 to 5 bar). Thereaction is generally carried out at atmospheric pressure.

Alternatively, compounds of the formula (I) in which X represents O canbe obtained from compounds of the formula (II-B) by reaction withcompounds of the formula (VI)

in which R¹ and R² have the meanings given above.

Suitable inert solvents for the reaction (II-B)+(VI)→(I) are inparticular acyclic and cyclic ethers such as diethyl ether, methyltert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane,hydrocarbons, such as benzene, toluene, xylene, hexane and cyclohexane,or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide(DMSO), N-methylpyrrolidinone (NMP) and pyridine. It is also possible touse mixtures of the solvents mentioned above. Preference is given tousing dimethylformamide.

Suitable bases for this reaction are in particular alkali metalalkoxides, such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or sodium tert-butoxide or potassiumtert-butoxide, alkali metal hydrides, such as lithium hydride, sodiumhydride or potassium hydride, amides, such as sodium amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, or organometalliccompounds, such as butyllithium or phenyllithium. Preference is given tousing potassium tert-butoxide.

Here, the base is generally employed in an amount of from 1 to 1.25 mol,preferably in an equimolar amount, based on 1 mol of the compound of theformula (VI).

The reactions (II-B)+(VI)→(I) are generally carried out in a temperaturerange of from −20° C. to +120° C., preferably at from +20° C. to +100°C., if appropriate in a microwave oven. The reaction can be carried outat atmospheric, elevated or reduced pressure (for example in the rangefrom 0.5 to 5 bar). The reaction is generally carried out at atmosphericpressure.

The compounds of the formulae (IV) and (VI) are commercially available,known from the litreature or can be prepared by methods known from thelitreature.

The compounds of the formula (V) are commercially available, known fromthe litreature or can be prepared by methods known from the litreature.Thus, for example, 2-substituted oxazole and thiazole derivatives of theformulae (V-A), (V-B) and (V-C) can be obtained by reaction of amides,thioamides and thiourea derivatives, respectively, with a1,3-dihaloacetone (see Scheme 3):

In the case of the compounds (V-C), these can be prepared and isolatedeither analogously to the litreature [cf., for example, I. Simiti etal., Chem. Ber. 95, 2672-2679 (1962)], or they can be generated in situand directly reacted further. Preferred is the in situ generation using1,3-dichloroacetone in the solvent dimethylformamide or ethanol. Thepreparation is generally carried out in a temperature range of from 0°C. to +140° C., preferably in the range from +20° C. to +120° C., inparticular at from +60° C. to +100° C.

Compounds of the formula (II-A) where X represents S can be preparedanalogously to methods known from the literature, for example byreacting aldehydes of the formula (VII)

in which

-   R^(3A) represents phenyl or 5- or 6-membered heteroaryl which is    attached via carbon    -   where phenyl and 5- or 6-membered heteroaryl which is attached        via carbon may be substituted within the scope of the meaning        given above,        in the presence of a base with two equivalents of        cyanothioacetamide to give compounds of the formula (VIII)

in which R^(3A) has the meaning given above,and subsequently reacting these in an inert solvent in the presence of abase with a compound of the formula (V) [see Schema 4; cf., for example,Dyachenko et al., Russ. J. Chem. 33 (7), 1014-1017 (1997), 34 (4),557-563 (1998); Dyachenko et al., Chemistry of Heterocyclic Compounds 34(2), 188-194 (1998); Qintela et al., Eur. J. Med. Chem. 33, 887-897(1998); Kandeel et al., Z. Naturforsch. 42b, 107-111 (1987); Reddy etal., J. Med. Chem. 49, 607-615 (2006); Evdokimov et al., Org. Lett. 8,899-902 (2006)].

The compounds of the formula (VII) are commercially available, knownfrom the litreature or can be prepared by methods known from thelitreature.

For the reaction (VIII)→(II-A), the conditions mentioned for processstep (III-B)+(V)→(I) are used.

Compounds of the formula (II-A) where X represents O can be obtainedfrom compounds of the formula (IX)

in which R³ has the meaning given above,by reaction in an inert solvent in the presence of a suitable base witha compound of the formula (VI).

For this process step, the conditions mentioned for the reaction(II-B)+(VI)→(I) are used.

This preparation method is illustrated by the reaction scheme below:

The compounds of the formula (IX) can be prepared analogously toprocesses described in the litreature [cf., for example, Kambe et al.,Synthesis, 531-533 (1981); Elnagdi et al., Z. Naturforsch. 47b, 572-578(1991); Reddy et al., J. Med. Chem. 49, 607-615 (2006); Evdokimov etal., Org. Lett. 8, 899-902 (2006)] or by reacting compounds of theformula (II) in which X represents S analogously to processes describedin the litreature [cf., for example, Fujiwara, H. et al., Heterocycles1993, 36 (5), 1105-1113, Su et al., J. Med. Chem. 1988, 31, 1209-1215].

Compounds of the formula (II-B) can be prepared by converting compoundsof the formula (VII) in a suitable solvent in the presence of a suitablebase with 2 equivalents of malononitrile and compounds of the formula(X)

R⁴—O⁻M⁺  (X),

in which R⁴ has the meaning given above and

-   M⁺ represents ein alkali metal ion, preferably a sodium or potassium    ion,    into compounds of the formula (XI)

in which R^(3A) and R⁴ each have the meanings given above,and then reacting these with copper(II) chloride and isoamyl nitrite ina suitable solvent.

The process described is illustrated in an exemplary manner by thereaction scheme below:

Further compounds of the formula (II-A) in which X represents S can beprepared by converting the compound of the formula (XII)

in an inert solvent in the presence of a base with a compound of theformula (V) into a compound of the formula (XIII)

in which R¹ and R² have the meanings given above,and then reacting this in an inert solvent or in the absence of asolvent with a compound of the formula (XIV)

R^(3B)—H  (XIV),

in which

-   R^(3B) represents 5- or 6-membered heteroaryl which is attached via    nitrogen,    -   where 5- or 6-membered heteroaryl which is attached via nitrogen        may be substituted within the scope of the meaning given above        for R³.

The reaction (XII)+(V)→(XIII) is carried out under the conditionsmentioned for process step (III-B)+(V)→(I).

Suitable solvents for the process step (XIII)+(XIV) are all organicsolvents which are inert under the reaction conditions. These includealcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanoland tert-butanol, ketones, such as acetone and methyl ethyl ketone,acyclic and cyclic ethers, such as diethyl ether, methyl tert-butylether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, esters, such asethyl acetate or butyl acetate, hydrocarbons, such as benzene, toluene,xylene, hexane and cyclohexane, chlorinated hydrocarbons, such asdichloromethane and chlorobenzene, or other solvents, such asdimethylformamide (DMF), dimethyl sulfoxide (DMSO),N-methylpyrrolidinone (NMP), acetonitrile and pyridine. Another suitablesolvent is water. It is also possible to use mixtures of the solventsmentioned above. If appropriate, the reaction can also advantageously becarried out in the presence of an excess of the compound (XIV) withoutaddition of a further solvent. The reaction is preferably carried out inthe solvent acetone or N-methylpyrrolidinone.

The process step (XIII)+(XIV) is generally carried out in a temperaturerange of from 0° C. to +180° C., preferably in the range from +20° C. to+100° C., in particular at from +60° C. to +100° C., if appropriate in amicrowave oven. The reaction can be carried out at atmospheric, elevatedor reduced pressure (for example in the range from 0.5 to 5 bar). Thereaction is generally carried out at atmospheric pressure.

The compounds of the formula (XIV) are commercially available, knownfrom the litreature or can be prepared by methods known from thelitreature.

The compound of the formula (XII) can be obtained in a simple manner byreacting [bis(methylthio)methylene]malononitrile with cyanothioacetamidein the presence of a base such as triethylamine.

Further compounds of the formula (II-A) in which X represents O can beprepared by converting the compound of the formula (XV)

in which

-   R⁶ represents (C₁-C₄)-alkyl or phenyl,    in an inert solvent in the presence of a base with a compound of the    formula (VI) into a compound of the formula (XVI)

in which R¹ and R² have the meanings given above,and then reacting this in an inert solvent or in the absence of asolvent with a compound of the formula (XIV), oralternatively reacting a compound of the formula (XV) initially in aninert solvent or in the absence of a solvent with a compound of theformula (XIV) to give compounds of the formula (XVII)

in which R^(3B) and R⁶ each have the meanings given above,and then reacting these in an inert solvent in the presence of asuitable base with a compound of the formula (VI).

The compounds of the formula (XV), in which R⁶ represents phenyl can beprepared from the compound of the formula (XII) analogously to theprocess described in Fujiwara, H. et al., Heterocycles 1993, 36 (5),1105-1113.

The compounds of the formula (XV) in which R⁶ represents (C₁-C₄)-alkylcan be prepared from the compound of the formula (XII) analogously tothe process described in Su et al., J. Med. Chem. 1988, 31, 1209-1215.

The reaction (XV)+(VI) is carried out under the conditions mentioned forprocess step (II-B)+(VI)→(I).

Suitable solvents for the process steps (XV) and (XVI)+(XIV) are allorganic solvents which are inert under the reaction conditions. Theseinclude alcohols, such as methanol, ethanol, n-propanol, isopropanol,n-butanol and tert-butanol, ketones, such as acetone and methyl ethylketone, acyclic and cyclic ethers, such as diethyl ether, methyltert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane,esters, such as ethyl acetate or butyl acetate, hydrocarbons, such asbenzene, toluene, xylene, hexane and cyclohexane, chlorinatedhydrocarbons, such as dichloromethane and chlorobenzene, or othersolvents, such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO),N-methylpyrrolidinone (NMP), acetonitrile and pyridine. Another suitablesolvent is water. It is also possible to use mixtures of the solventsmentioned above. If appropriate, the reaction can also advantageously becarried out in the presence of an excess of the compound (XIV) withoutaddition of a further solvent. The reaction is preferably carried out inthe solvent acetone or N-methylpyrrolidinone.

The process step (XV) or (XVI)+(XIV) is generally carried out in atemperature range of from 0° C. to +180° C., preferably in the rangefrom +20° C. to +100° C., in particular at from +60° C. to +100° C., ifappropriate in a microwave oven. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example in the range from0.5 to 5 bar). The reaction is generally carried out at atmosphericpressure.

The processes described above are illustrated in the schemes below:

Other compounds according to the invention can, if appropriate, also beprepared by converting functional groups of individual substituents, inparticular those listed under R¹, R², R³, R⁴ and R⁵, starting with thecompounds of the formula (I) obtained by the above processes. Theseconversions are carried out by customary methods known to the personskilled in the art and include, for example, reactions such asnucleophilic and electrophilic substitutions, oxidations, reductions,hydrogenations, transition metal-catalyzed coupling reactions,eliminations, alkylation, amination, esterification, ester cleavage,etherification, ether cleavage, formation of carboxamides, and also theintroduction and removal of temporary protective groups.

Compared to the substances known from the prior art, the compoundsaccording to the invention have an improved property profile, such as,for example, increased solubility in aqueous-organic solvent systemswhich are relevant for the formulation, a longer pharmacokinetichalf-life after oral administration and/or increased metabolicstability.

In the context of the present invention, “selective ligands at adenosineA1 and/or A2b receptors” are adenosine receptor ligands where firstly amarked activity at A1 and/or A2b adenosine receptor subtypes andsecondly no or a considerably weaker activity (by a factor of 10 ormore) at A2a and A3 adenosine receptor subtypes can be observed, wherewith respect to the test methods for activity/selectivity, reference ismade to the tests described in section B-1.

Surprisingly, the compounds according to the invention have anunforeseeable useful pharmacological activity spectrum and are thereforeparticularly suitable for the prophylaxis and/or treatment of disorders.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their action as potent, selective ligands atadenosine A1 and/or A2b receptors. Here, they act as selective A1agonists, as selective dual A1/A2b agonists or as selective A1antagonists. The compounds according to the invention have an identicalor improved physicochemical, pharmacokinetic and/or therapeutic profile.The compounds according to the invention act mainly as selectiveadenosine A1 agonists.

In the context of the present invention, “selective ligands at adenosineA1 and/or A2b receptors” are adenosine receptor ligands where firstly amarked activity at A1 and/or A2b adenosine receptor subtypes andsecondly no or a considerably weaker activity (by a factor of 10 ormore) at A2a and A3 adenosine receptor subtypes can be observed, wherewith respect to the test methods for activity/selectivity, reference ismade to the tests described in sections B-1 and B-5.

Depending on their particular structure, the compounds according to theinvention can act as full or as partial adenosine receptor agonists oras adenosine receptor antagonists. Partial adenosine receptor agonistsare defined here as receptor ligands which trigger a functional responseat adenosine receptors which is less than that of full agonists (suchas, for example, adenosine itself). Accordingly, partial agonists havelower activity with respect to receptor activation than full agonists.

The compounds of the formula (I) are suitable alone or in combinationwith one or more other active ingredients for the prophylaxis and/ortreatment of various disorders, for example disorders of thecardiovascular system (cardiovascular disorders), for cardio protectionfollowing lesions of the heart, and of metabolic disorders and kidneydisorders.

Disorders of the cardiovascular system, or cardiovascular disorders,mean in the context of the present invention for example the followingdisorders: hypertension, peripheral and cardiac vascular disorders,coronary heart disease, coronary restenosis such as, for example,restenosis following balloon dilatation of peripheral blood vessels,myocardial infarction, acute coronary syndrome, acute coronary syndromewith ST elevation, acute coronary syndrome without ST elevation, stableand unstable angina pectoris, myocardial insufficiency, princemetalangina, persistent ischemic dysfunction (“hibernating myocardium”),temporary postischemic dysfunction (“stunned myocardium”), heartfailure, tachycardia, atrial tachycardia, arrhythmias, atrial andventricular fibrillation, persistent atrial fibrillation, permanentatrial fibrillation, atrial fibrillation with normal left ventricularfunction, atrial fibrillation with impaired left ventricular function,Wolff-Parkinson-White syndrome, disturbances of peripheral blood flow,elevated levels of fibrinogen and of low density LDL, and elevatedconcentrations of plasminogen activator inhibitor 1 (PAI-1), especiallycoronary heart disease, acute coronary syndrome, angina pectoris, heartfailure, myocardial infarction and atrial fibrillation.

In the context of the present invention, the term heart failure includesboth acute and chronic manifestations of heart failure, as well as morespecific or related types of disease, such as acute decompensated heartfailure, right heart failure, left heart failure, global failure,ischemic cardiomyopathy, dilated cardiomyopathy, congenital heartdefects, heart valve defects, heart failure associated with heart valvedefects, mitral stenosis, mitral insufficiency, aortic stenosis, aorticinsufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonarystenosis, pulmonary valve insufficiency, combined heart valve defects,myocardial inflammation (myocarditis), chronic myocarditis, acutemyocarditis, viral myocarditis, diabetic heart failure, alcoholiccardiomyopathy, cardiac storage disorders, and diastolic and systolicheart failure.

The compounds according to the invention are further also suitable forreducing the area of myocardium affected by an infarction, and for theprophylaxis of secondary infarctions.

The compounds according to the invention are furthermore suitable forthe prophylaxis and/or treatment of thromboembolic disorders,reperfusion damage following ischemia, micro- and macrovascular lesions(vasculitis), arterial and venous thromboses, edemas, ischemias such asmyocardial infarction, stroke and transient ischemic attacks, for cardioprotection in connection with coronary artery bypass operations (CABG),primary PTCAs, PTCAs after thrombolysis, rescue PTCA, heart transplantsand open-heart operations, and for organ protection in connection withtransplants, bypass operations, catheter examinations and other surgicalprocedures.

Furthermore, the compounds according to the invention are suitable forthe treatment and/or prevention of kidney diseases, in particular ofrenal insufficiency. In the context of the present invention, the termrenal insufficiency comprises both acute and chronic manifestations ofrenal insufficiency, as well as underlying or related kidney diseasessuch as renal hypoperfusion, obstructive uropathy, glomerulonephritis,acute glomerulonephritis, tubulointerstitial diseases, nephropathicdiseases such as primary and congenital kidney disease, nephritis,nephropathy induced by toxic substances, diabetic nephropathy,pyelonephritis, renal cysts and nephrosclerosis, which can becharacterized diagnostically for example by abnormally reducedcreatinine and/or water excretion, abnormally raised bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, such as, for example, glutamylsynthetase,altered urine osmolarity or urine volume, increased microalbuminuria,macroalbuminuria, lesions on glomeruli and arterioles, tubulardilatation, hyperphosphatemia and/or need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prevention of sequelae of renalinsufficiency, for example pulmonary edema, heart failure, uraemia,anemia, electrolyte disturbances (for example hyperkalemia,hyponatremia) and disturbances in bone and carbohydrate metabolism.

Other areas of indication for which the compounds according to theinvention can be employed are, for example, the prevention and/ortreatment of disorders of the urogenital tract, such as, for example,irritable bladder, erectile dysfunction and female sexual dysfunction,but in addition also the prevention and/or treatment of inflammatorydisorders, such as, for example, inflammatory dermatoses (psoriasis,acne, eczema, neurodermitis, dermatitis, keratitis, formation of scars,formation of warts, frostbites), of disorders of the central nervoussystem and neurodegenerative disorders (strokes, Alzheimer's disease,Parkinson's disease, dementia, epilepsy, depression, multiplesclerosis), of states of pain, cancerous diseases (skin cancer,liposarcomas, carcinomas of the gastrointestinal tract, the liver,pancreas, lung, kidney, ureter, prostate and the genital tract), andalso of nausea and emesis associated with cancer therapies.

Other areas of indication are, for example, the prevention and/ortreatment of inflammatory and immune disorders (Crohn's disease,ulcerative colitis, lupus erythematodes, rheumatoid arthritis) andrespiratory disorders, such as, for example, chronic obstructivepulmonary disease (chronic bronchitis, COPD), asthma, pulmonaryemphysema, bronchiectases, cystic fibrosis (mucoviscidosis) andpulmonary hypertension, in particular pulmonary arterial hypertension.

Finally, the compounds according to the invention are also suitable forthe prevention and/or treatment of diabetes, in particular diabetesmellitus, gestation diabetes, insulin-dependent diabetes andnon-insulin-dependent diabetes, of diabetic sequelae such as, forexample, retinopathy, nephropathy and neuropathy, of metabolic disorders(metabolic syndrome, hyperglycemia, gestational diabetes,hyperinsulinemia, insulin resistance, glucose intolerance, obesity(adipositas)) and also of arteriosclerosis and dyslipidemias(hypercholesterolemia, hypertriglyceridemia, elevated concentrations ofpostprandial plasma triglycerides, hypoalphalipoproteinemia, combinedhyperlipidemias), in particular of diabetes, metabolic syndrome anddyslipidemias.

In addition, the compounds according to the invention can also be usedfor the treatment and/or prevention of disorders of the thyroid gland(hyperthyreosis), disorders of the pancreas (pancreatitis), fibrosis ofthe liver, viral diseases (HPV, HCMV, HIV), cachexia, osteoporosis,gout, incontinence, and also for wound healing and angiogenesis.

The present invention furthermore provides the use of the compoundsaccording to the invention for the treatment and/or prevention ofdisorders, in particular the disorders mentioned above.

The present invention furthermore provides the use of the compoundsaccording to the invention for preparing a medicament for the treatmentand/or prevention of disorders, in particular the disorders mentionedabove.

The present invention furthermore provides a method for the treatmentand/or prevention of disorders, in particular the disorders mentionedabove, using an effective amount of at least one of the compoundsaccording to the invention.

The present invention furthermore provides the compounds according tothe invention for use in a method for the treatment and/or prophylaxisof coronary heart disease, acute coronary syndrome, angina pectoris,heart failure, myocardial infarction and atrial fibrillation.

The present invention furthermore provides the compounds according tothe invention for methods for the treatment and/or prophylaxis ofdiabetes, metabolic syndrome and dyslipidemias.

The compounds according to the invention can be used alone or, ifrequired, in combination with other active ingredients. The presentinvention furthermore provides medicaments comprising at least one ofthe compounds according to the invention and one or more further activeingredients, in particular for the treatment and/or prevention of thedisorders mentioned above.

Suitable active ingredients for combination are, by way of example andby way of preference: active ingredients which modulate lipidmetabolism, antidiabetics, hypotensive agents, perfusion-enhancingand/or antithrombotic agents, antioxidants, chemokine receptorantagonists, p38-kinase inhibitors, NPY agonists, orexin agonists,anorectics, PAF-AH inhibitors, antiphlogistics (COX inhibitors,LTB₄-receptor antagonists), analgesics for example aspirin,antidepressants and other psychopharmaceuticals.

The present invention relates in particular to combinations of at leastone of the compounds according to the invention with at least one lipidmetabolism-altering active ingredient, antidiabetic, bloodpressure-reducing active ingredient and/or agent having antithromboticeffects.

The compounds according to the invention can preferably be combined withone or more

-   -   lipid metabolism-modulating active ingredients, by way of        example and by way of preference from the group of the HMG-CoA        reductase inhibitors, inhibitors of HMG-CoA reductase        expression, squalene synthesis inhibitors, ACAT inhibitors, LDL        receptor inductors, cholesterol absorption inhibitors, polymeric        bile acid adsorbers, bile acid reabsorption inhibitors, MTP        inhibitors, lipase inhibitors, LpL activators, fibrates, niacin,        CETP inhibitors, PPAR-α, PPAR-γ and/or PPAR-γ agonists, RXR        modulators, FXR modulators, LXR modulators, thyroid hormones        and/or thyroid mimetics, ATP citrate lyase inhibitors, Lp(a)        antagonists, cannabinoid receptor 1 antagonists, leptin receptor        agonists, bombesin receptor agonists, histamine receptor        agonists and the antioxidants/radical scavengers;    -   antidiabetics mentioned in the Rote Liste 2004/II, chapter 12,        and also, by way of example and by way of preference, those from        the group of the sulphonylureas, biguanides, meglitinide        derivatives, glucosidase inhibitors, inhibitors of        dipeptidyl-peptidase IV (DPP-IV inhibitors), oxadiazolidinones,        thiazolidinediones, GLP 1 receptor agonists, glucagon        antagonists, insulin sensitizers, CCK 1 receptor agonists,        leptin receptor agonists, inhibitors of liver enzymes involved        in the stimulation of gluconeogenesis and/or glycogenolysis,        modulators of glucose uptake and also potassium channel openers,        such as, for example, those disclosed in WO 97/26265 and WO        99/03861;    -   hypotensive active ingredients, by way of example and by way of        preference from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, renin inhibitors,        beta-receptor blockers, alpha-receptor blockers, aldosterone        antagonists, mineralocorticoid receptor antagonists, ECE        inhibitors, ACE/NEP inhibitors and the vasopeptidase inhibitors;        and/or    -   antithrombotic agents, by way of example and by way of        preference from the group of the platelet aggregation inhibitors        or the anticoagulants;    -   diuretics;    -   vasopressin receptor antagonists;    -   organic nitrates and NO donors;    -   compounds with positive inotropic activity;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), such as, for example, inhibitors of phosphodiesterases        (PDE) 1, 2, 3, 4 and/or 5, in particular PDE 5 inhibitors, such        as sildenafil, vardenafil and tadalafil, and also PDE 3        inhibitors, such as milrinone;    -   natriuretic peptides, such as, for example, “atrial natriuretic        peptide” (ANP, anaritide), “B-type natriuretic peptide” or        “brain natriuretic peptide” (BNP, nesiritide), “C-type        natriuretic peptide” (CNP) and also urodilatin;    -   agonists of the prostacyclin receptor (IP receptor), such as, by        way of example, iloprost, beraprost, cicaprost;    -   inhibitors of the I_(f) (funny channel) channel, such as, by way        of example, ivabradine;    -   calcium sensitizers, such as, by way of example and by way of        preference, levosimendan;    -   potassium supplements;    -   NO-independent, and heme-independent activators of guanylate        cyclase, such as, in particular, cinaciguate and the compounds        described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780,        WO 02/070462 and WO 02/070510;    -   NO-independent but heme-dependent stimulators of guanylate        cyclase, such as, in particular, riociguate and the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301 and WO        03/095451;    -   inhibitors of human neutrophil elastase (HNE), such as, for        example, sivelestat and DX-890 (Reltran);    -   compounds which inhibit the signal transduction cascade, such        as, for example, tyrosine-kinase inhibitors, in particular        sorafenib, imatinib, gefitinib and erlotinib; and/or    -   compounds which modulate the energy metabolism of the heart,        such as, for example, etomoxir, dichloroacetate, ranolazine and        trimetazidine.

Lipid metabolism-modifying active ingredients are to be understood asmeaning, preferably, compounds from the group of the HMG-CoA reductaseinhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterolabsorption inhibitors, MTP inhibitors, lipase inhibitors, thyroidhormones and/or thyroid mimetics, niacin receptor agonists, CETPinhibitors, PPAR-α agonists, PPAR-γ agonists, PPAR-γ agonists, polymericbile acid adsorbers, bile acid reabsorption inhibitors,antioxidants/radical scavengers and also the cannabinoid receptor 1antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of the statins, such as, by way of example andby way of preference, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, such as, by way of example and by way of preference,BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor,such as, by way of example and by way of preference, avasimibe,melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, such as, by way of example and by way ofpreference, ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor,such as, by way of example and by way of preference, implitapide,BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,such as, by way of example and by way of preference, orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid hormoneand/or thyroid mimetic, such as, by way of example and by way ofpreference, D-thyroxine or 3,5,3′-triiodothyronine (T3).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an agonist of theniacin receptor, such as, by way of example and by way of preference,niacin, acipimox, acifran or radecol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor,such as, by way of example and by way of preference, dalcetrapib, BAY60-5521, anacetrapib or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-γ agonist forexample from the class of the thiazolidinediones, such as, by way ofexample and by way of preference, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-δ agonist suchas, by way of example and by way of preference, GW-501516 or BAY68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorber, such as, by way of example and by way of preference,cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor, such as, by way of example and by way ofpreference, ASBT (=IBAT) inhibitors, such as, for example, AZD-7806,S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with anantioxidant/radical scavenger, such as, by way of example and by way ofpreference, probucol, AGI-1067, BO-653 or AEOL-10150.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cannabinoidreceptor 1 antagonist, such as, by way of example and by way ofpreference, rimonabant or SR-147778.

Antidiabetics are to be understood as meaning, preferably, insulin andinsulin derivatives, and also orally effective hypoglycemic activeingredients. Here, insulin and insulin derivatives include both insulinsof animal, human or biotechnological origin and also mixtures thereof.The orally effective hypoglycemic active ingredients preferably includesulphonylureas, biguanides, meglitinide derivatives, glucosidaseinhibitors and PPAR-gamma agonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with insulin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a sulphonylurea, suchas, by way of example and by way of preference, tolbutamide,glibenclamide, glimepiride, glipizide or gliclazide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a biguanide, such as,by way of example and by way of preference, metformin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a meglitinidederivative, such as, by way of example and by way of preference,repaglinide or nateglinide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a glucosidaseinhibitor, such as, by way of example and by way of preference, miglitolor acarbose.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a DPP-IV inhibitor,such as, by way of example and by way of preference, sitagliptin andvildagliptin.

The hypotensive agents are preferably understood as meaning compoundsfrom the group of the calcium antagonists, angiotensin AII antagonists,ACE inhibitors, beta-receptor blockers, alpha-receptor blockers anddiuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,such as, by way of example and by way of preference, nifedipine,amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist, such as, by way of example and by way of preference,losartan, valsartan, candesartan, embusartan, olmesartan or telmisartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor,such as, by way of example and by way of preference, enalapril,captopril, lisinopril, ramipril, delapril, fosinopril, quinopril,perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker, such as, by way of example and by way of preference,propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol,penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol,sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol,esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol,epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-receptorblocker, such as, by way of example and by way of preference, prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such as,by way of example and by way of preference, furosemide, bumetanide,torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide,chlorothalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamteren.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an aldosterone ormineralocorticoid receptor antagonist, such as, by way of example and byway of preference, spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vasopressinreceptor antagonist, such as, by way of example and by way ofpreference, conivaptan, tolvaptan, lixivaptan or SR-121463.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an organic nitrate orNO donor, such as, by way of example and by way of preference, sodiumnitroprusside, nitroglycerol, isosorbide mononitrate, isosorbidedinitrate, molsidomin or SIN-1, or in combination with inhalative NO.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a positive-inotropiccompound, such as, by way of example and by way of preference, cardiacglycosides (digoxin), beta-adrenergic and dopaminergic agonists, such asisoproterenol, adrenaline, noradrenaline, dopamine or dobutamine.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with antisympathotonics,such as reserpine, clonidine or alpha-methyldopa, or in combination withpotassium channel agonists, such as minoxidil, diazoxide, dihydralazineor hydralazine, or with substances which release nitrogen oxide, such asglycerol nitrate or sodium nitroprusside.

Antithrombotics are to be understood as meaning, preferably, compoundsfrom the group of the platelet aggregation inhibitors or theanticoagulants.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, such as, by way of example and by way ofpreference, aspirin, clopidogrel, ticlopidine or dipyridamol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,such as, by way of example and by way of preference, ximelagatran,melagatran, dabigatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, such as, by way of example and by way of preference,tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, such as, by way of example and by way of preference,rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban,razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982,EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 orSSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, such as, by way of example and by way of preference,coumarin.

In the context of the present invention, particular preference is givento combinations comprising at least one of the compounds according tothe invention and also one or more further active ingredients selectedfrom the group consisting of HMG-CoA reductase inhibitors (statins),diuretics, beta-receptor blockers, organic nitrates and NO donors, ACEinhibitors, angiotensin AII antagonists, aldosterone andmineralocorticoid receptor antagonists, vasopressin receptorantagonists, platelet aggregation inhibitors and anticoagulants, andalso their use for the treatment and/or prevention of the disordersmentioned above.

The present invention furthermore provides medicaments comprising atleast one compound according to the invention, usually together with oneor more inert, nontoxic, pharmaceutically suitable auxiliaries, and alsotheir use for the purposes mentioned above.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, such as, for example, orally, parenterally, pulmonally, nasally,sublingually, lingually, buccally, rectally, dermally, transdermally,conjunctivally, otically or as an implant or stent.

For these administration routes, the compounds according to theinvention can be administered in suitable administration forms.

Suitable for oral administration are administration forms which work inaccordance with the prior art and release the compounds according to theinvention rapidly and/or in modified form and which comprise thecompounds according to the invention in crystalline and/or amorphicizedand/or dissolved form, such as, for example, tablets (uncoated or coatedtablets, for example with enteric coats or coats which dissolve in adelayed manner or are insoluble and which control the release of thecompound according to the invention), films/wafers or tablets whichdissolve rapidly in the oral cavity, films/lyophilizates, capsules (forexample hard or soft gelatin capsules), sugar-coated tablets, granules,pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may take place by circumventing abioabsorption step (for example intravenously, intraarterially,intracardially, intraspinally or intralumbarly), or with bioabsorption(for example intramuscularly, subcutaneously, intracutaneously,percutaneously or intraperitoneally). Administration forms suitable forparenteral administration are inter alia preparations for injection orinfusion in the form of solutions, suspensions, emulsions, lyophilizatesor sterile powders.

Suitable for other administration routes are, for example, medicamentssuitable for inhalation (inter alia powder inhalers, nebulizers), nosedrops, solutions or sprays, tablets to be administered lingually,sublingually or buccally, films/wafers or capsules, suppositories,preparations to be administered to ears or eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (for exampleplasters), milk, pastes, foams, powders for pouring, implants or stents.

Preference is given to oral or parenteral administration, in particularto oral and intravenous administration.

The compounds according to the invention can be converted into theadministration forms mentioned. This can be carried out in a mannerknown per se by mixing with inert, non-toxic, pharmaceutically suitableauxiliaries. These auxiliaries include inter alia carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (for exampleliquid polyethylene glycols), emulsifiers and dispersants or wettingagents (for example sodium dodecyl sulphate, polyoxysorbitan oleate),binders (for example polyvinylpyrrolidone), synthetic and naturalpolymers (for example albumin), stabilizers (for example antioxidants,such as, for example, ascorbic acid), colorants (for example inorganicpigments, such as, for example, iron oxides), and flavor and/or odorcorrigents.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to obtaineffective results. In the case of oral administration, the dosage isfrom about 0.01 to 100 mg/kg, preferably from about 0.01 to 20 mg/kg andvery particularly preferably from 0.1 to 10 mg/kg of body weight.

In spite of this, it may be necessary to deviate from the amountsmentioned, namely depending on body weight, administration route,individual response to the active ingredient, the type of preparationand the time or the interval at which administration takes place. Thus,in some cases it may be sufficient to administer less than theabovementioned minimum amount, whereas in other cases the upper limitmentioned has to be exceeded. In the case of the administration ofrelatively large amounts, it may be expedient to divide these into aplurality of individual doses which are administered over the course ofthe day.

The working examples below illustrate the invention. The invention isnot limited to the examples.

The percentages in the tests and examples below are, unless indicatedotherwise, percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentrations of liquid/liquid solutionsare in each case based on volume.

A. EXAMPLES Abbreviations Used

-   aq. aqueous-   Ex. Example-   c concentration-   d doublet (in NMR)-   dd doublet of doublets (in NMR)-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   TLC thin-layer chromatography-   DCI direct chemical ionization (in MS)-   DMF N,N-dimethylformamide-   DMSO dimethyl sulphoxide-   ee enantiomeric excess-   EI electron impact ionization (in MS)-   ESI electrospray ionization (in MS)-   Et ethyl-   m.p. melting point-   h hour(s)-   HPLC high-pressure, high-performance liquid chromatography-   cat. catalytic-   conc. concentrated-   LC-MS liquid chromatography-coupled mass spectrometry-   lit. litreature (reference)-   Me methyl-   MeCN acetonitrile-   min minute(s)-   MS mass spectrometry-   NMM N-methylmorpholine-   NMR nuclear magnetic resonance spectrometry-   q quartet (in NMR)-   rac. racemic-   RP-HPLC reversed-phase HPLC-   RT room temperature-   R_(t) retention time (in HPLC)-   singlet (in NMR)-   br broad singlet (in NMR)-   t triplet (in NMR)-   t-Bu tert-butyl-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   dil. dilute

HPLC, LC-MS and GC-MS Methods:

Method 1 (LC-MS): MS instrument type: Waters (Micromass) Quattro Micro;HPLC instrument type: Agilent 1100 Series; column: Thermo Hypersil GOLD3μ 20×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formicacid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formicacid; gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100%A (flow rate 2.5 ml)→5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min;UV detection: 210 nm.

Method 2 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrumenttype: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flowrate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.;UV detection: 210 nm.

Method 3 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrumenttype: Waters Alliance 2795; column: Phenomenex Synergi 2.5μ MAX-RP 100AMercury 20 mm×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strengthformic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strengthformic acid; gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min5% A→4.01 min 90% A; flow rate: 2 ml/min; oven: 50° C.; UV detection:210 nm.

Method 4 (LC-MS): Instrument: Micromass Quattro Premier with Waters HPLCAcquity; column: Thermo Hypersil GOLD 1.9μ 50×1 mm; mobile phase A: 1 lof water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A; oven: 50° C.; flow rate:0.33 ml/min; UV detection: 210 nm.

Method 5 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrumenttype: Waters Alliance 2795; column: Phenomenex Synergi 2μ Hydro-RPMercury 20 mm×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strengthformic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strengthformic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 210 nm.

Method 6 (LC-MS): MS instrument type: Micromass ZQ; HPLC instrumenttype: Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e100×4.6 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formicacid; mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formicacid; gradient: 0.0 min 10% B→7.0 min 95% B→9.0 min 95% B; oven: 35° C.;flow rate: 0.0 min 1.0 ml/min→7.0 min 2.0 ml/min→9.0 min 2.0 ml/min; UVdetection: 210 nm.

Method 7 (preparative HPLC): column: Grom-Sil C18, 10 μm, 250 mm×30 mm.mobile phase A: water+0.1% formic acid, mobile phase B: acetonitrile.flow rate: 50 ml/min. program: 0-5 min: 10% B; 5-38 min: gradient to 95%B, UV detection: 210 nm.

Method 8 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC AgilentSeries 1100; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobilephase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flowrate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.;UV detection: 208-400 nm.

Method 9 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC AgilentSeries 1100; column: Phenomenex Onyx Monolithic C18, 100 mm×3 mm. mobilephase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phaseB: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0min 90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min;oven: 40° C.; UV detection: 208-400 nm.

Method 10 (LC-MS): MS instrument type: Waters ZQ; HPLC instrument type:Waters Alliance 2795; column: Phenomenex Onyx Monolithic C18, 100 mm×3mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate:2 ml/min; oven: 40° C.; UV detection: 210 nm.

Method 11 (LC-MS): MHZ-Q-GEM-1 MS instrument type: Micromass QuattroLCZ; HPLC instrument type: HP 1100 Series; UV DAD; column: PhenomenexGemini 3μ 30 mm×3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50%strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%strength formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5%A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min. 2ml/min; oven: 50° C.; UV detection: 210 nm.

Starting Materials and Intermediates Example 1A2-Amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile

The preparation was carried out as described in WO 03/053441 for Example6.

MS (ESIpos): m/z=253 [M+H]⁺

Example 2A2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile

2 g (7.927 mmol) of2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile are initiallycharged in 15 ml of DMF, 2.13 g (8.720 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.99 g (23.781mmol) of sodium bicarbonate are added and the mixture is stirred at roomtemperature overnight. Water is added to the reaction mixture, and theprecipitated solid is filtered off, washed with MTBE and dried underhigh vacuum. This gives 3.87 g (100% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.14 (s br, 2H), 7.97-7.92 (m, 3H),7.59-7.50 (m, 7H), 4.64 (s, 2H).

LC-MS (Method 4): R_(t)=1.49 min; MS (ESIpos): m/z=460 [M+H]⁺.

Example 3A2-Chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile

9 g (19.762 mmol) of2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrileare initially charged in 200 ml of acetonitrile, 7.98 ml (59.285 mmol)of isoamyl nitrite and 7.97 g (59.285 mmol) of copper(II) chloride areadded and the mixture is stirred at 60° C. for 4 hours. 1N Hydrochloricacid is added to the mixture, and the precipitated solid is filteredoff. It is purified on a silica gel column (mobile phase: toluene). Thisgives 5.98 g (63% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.96 (d, 2H), 7.76 (s, 1H), 7.66-7.62 (m,5H), 7.57 (d, 2H), 4.78 (s, 2H).

LC-MS (Method 3): R_(t)=2.82 min; MS (ESIpos): m/z=479 [M+H]⁺.

Example 4A2-Chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitrile

The preparation was carried out analogously to Example 3A from theappropriate starting materials.

LC-MS (Method 2): R_(t)=2.93 min; MS (ESIpos): m/z=539 [M+H]⁺.

Example 5A2-Amino-6-sulphanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile

1.14 g (9.539 mmol) of 5-thiazolecarboxaldehyde and 1.91 g (19.077 mmol)of cyanothioacetamide are initially charged in 20 ml of ethanol, 2.097ml (19.077 mmol) of 4-methylmorpholine are added and the mixture isheated under reflux for 4 hours. The mixture is then stirred at roomtemperature for 20 hours. The reaction mixture is concentrated and theresidue is purified on silica gel (mobile phase: methylenechloride/methanol 100:0→10:1). The product-containing fractions areconcentrated and the residue is triturated with acetonitrile. The solidis filtered off and dried under high vacuum. This gives 920 mg (37% oftheory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=9.31 (s, 1H), 8.16 (s, 1H), 7.50-6.99 (sbr, 2H).

LC-MS (Method 2): R_(t)=1.29 min; MS (ESIpos): m/z=260 [M+H]⁺.

Example 6A2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile

370 mg (1.427 mmol) of2-amino-6-sulphanyl-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, 383mg (1.570 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and359 mg of sodium bicarbonate are stirred in 7 ml of DMF for 1 hour. 150ml of acetonitrile and 100 ml of water are added to the reactionmixture, and the precipitated solid is filtered off and dried under highvacuum. This gives 569 mg (85% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=9.38 (s, 1H), 8.27 (s, 1H), 8.19-8.03 (sbr, 2H), 7.94 (d, 2H), 7.89 (s, 1H), 7.57 (d, 2H), 4.62 (s, 2H).

LC-MS (Method 2): R_(t)=2.67 min; MS (ESIpos): m/z=467 [M+H]⁺.

Example 7A2-Chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile

569 mg (1.218 mmol) of2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrileare dissolved in 20 ml of concentrated hydrochloric acid, the mixture iscooled to 0° C. and 252 mg (3.655 mmol) of sodium nitrite are added atthis temperature. The mixture is stirred at 0° C. for 1 h and thenwarmed to room temperature and stirred at room temperature overnight.The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 445 mg (68% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=9.49 (s, 1H), 8.42 (s, 1H), 7.95 (d, 2H),7.75 (s, 1H), 7.58 (d, 2H), 4.78 (s, 2H).

LC-MS (Method 2): R_(t)=2.99 min; MS (ESIpos): m/z=486 [M+H]⁺.

Example 8A2-Amino-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

Under argon, 10 g (60.176 mmol) of 4-(2-hydroxyethoxy)benzaldehyde aredissolved in 125 ml of methanol, 8.15 g (123.362 mmol) of malononitrileand 19.506 g (361.058 mmol) of sodium methoxide are added and themixture is stirred at room temperature for 3 hours. The reaction mixtureis then concentrated, and the residue is taken up in ethyl acetate andwashed with saturated aqueous ammonium chloride solution. The organicphase is dried over sodium sulphate and concentrated. The residue istriturated with methanol, and the precipitated solid is filtered off anddried under high vacuum. This gives 5.2 g (22% of theory) of the targetcompound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.14-7.80 (s br, 2H), 7.46 (d, 2H), 7.10(d, 2H), 4.92 (t, 1H), 4.08 (t, 2H), 3.97 (s, 3H), 3.75 (q, 2H).

LC-MS (Method 4): R_(t)=0.86 min; MS (ESIpos): m/z=311 [M+H]⁺.

Example 9A2-Chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

3.3 g (10.634 mmol) of2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrileare initially charged in 300 ml of acetonitrile, 8.578 g (63.806 mmol)of copper(II) chloride and 8.59 ml (63.806 mmol) of isoamyl nitrite areadded and the mixture is stirred at room temperature overnight. 1Nhydrochloric acid is added, and the reaction mixture is extracted withethyl acetate. The organic phase is washed with saturated aqueous sodiumbicarbonate solution and water, dried over sodium sulphate andconcentrated. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 2.11 g (58% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.60 (d, 2H), 7.19 (d, 2H), 4.13 (s, 3H),4.11 (t, 2H), 3.75 (t, 2H).

LC-MS (Method 2): R_(t)=2.13 min; MS (ESIpos): m/z=330 [M+H]⁺.

Example 10A4-[4-(2-Hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile

4.0 g (12.1 mmol) of2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrileare dissolved in 16 ml of anhydrous DMF, 1.42 g (18.2 mmol) of anhydroussodium sulphide are added and the mixture is stirred at room temperaturefor 2 h. 36 ml of water are added, and with stirring the solution isslowly added dropwise to a mixture, warmed to 50° C., of 61 ml of 1Mhydrochloric acid and 20 ml of methanol. The yellow suspension isstirred at RT for 1 h and filtered off with suction, and the precipitateis washed with water and dried at 45° C. under reduced pressureovernight.

Yield: 3.27 g (82% of theory, purity 29%)

LC-MS (Method 6): R_(t)=3.27 min (29.4 Fl %); MS (ESIpos): m/z=328[M+H]⁺

The product is reacted further without further purification. Foranalytical purposes, a small sample is purified by preparative HPLC(Method 7):

¹H-NMR (500 MHz, DMSO-d₆): δ=7.59-7.48 (m, 2H), 7.20-7.10 (m, 2H),4.75-4.35 (br), 4.10 (t, 2H), 3.93 (s, 3H), 3.65 (t, 2H).

Example 11A 2-Mercapto-6-methoxy-4-phenylpyridine-3,5-dicarbonitrile

The preparation is carried out analogously to Example 10A from theappropriate starting materials.

LC-MS (Method 6): R_(t)=5.72 min; MS (ESIneg): m/z=266 [M−H]⁺.

Example 12A2-Amino-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile

40 g (240.705 mmol) of 4-(2-hydroxyethoxy)benzaldehyde are initiallycharged in 500 ml of ethanol, and 35.6 g (493.445 mmol) of malononitrileare added. 539 ml (1444.232 mmol) of 21% strength sodium methoxidesolution in ethanol are then added dropwise. The mixture is stirred atroom temperature for 24 hours. The mixture is concentrated, the residueis taken up in ethyl acetate and washed with water and saturated aqueoussodium chloride solution and the organic phase is dried over sodiumsulphate and concentrated. The residue is dissolved in ethanol, adsorbedonto silica gel and purified on silica gel (mobile phase: methylenechloride/ethanol 200:1→50:1). The product obtained is suspended in 200ml of ethanol, 1000 ml of water are added gradually and the mixture isstirred at room temperature for 1 hour. The solid is filtered off,washed with water/ethanol 1:1 and dried at 50° C. in a vacuum dryingcabinet. This gives 15.4 g (19% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.05-7.72 (s br, 2H), 7.46 (d, 2H), 7.10(d, 2H), 4.94 (t, 1H), 4.44 (q, 2H), 4.08 (t, 2H), 3.75 (q, 2H), 1.34(t, 3H).

LC-MS (Method 2): R_(t)=2.02 min; MS (ESIpos): m/z=325 [M+H]⁺.

Example 13A2-Chloro-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile

14.8 g (45.631 mmol) of2-amino-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrileare initially charged in 830 ml of acetonitrile, 32.07 g (273.785 mmol)of isoamyl nitrite and 36.81 g (273.785 mmol) of copper(II) chloride areadded and the mixture is stirred at 60° C. for 3 hours. 800 ml of 1Nhydrochloric acid are added, and the reaction mixture is extracted withethyl acetate. The organic phase is washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution,dried over sodium sulphate and concentrated. The residue is trituratedwith ethanol, and the solid is filtered off, washed with ethanol anddried under high vacuum. As the mother liquor still contains product, itis adsorbed onto 35 g of silica gel and purified on a silica gel column(mobile phase: cyclohexane/ethyl acetate 2:1→1:1). This gives a total of11.9 g (72% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.59 (d, 2H), 7.18 (d, 2H), 4.94 (s br,1H), 4.57 (q, 2H), 4.10 (t, 2H), 3.76 (t, 2H), 1.41 (t, 3H).

LC-MS (Method 8): R_(t)=2.30 min; MS (ESIpos): m/z=344 [M+H]⁺.

Example 14A2-Ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile

1 g (2.909 mmol) of2-chloro-6-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrileis initially charged in 7.5 ml of DMF, 454 mg (5.818 mmol) of sodiumsulphide are added and the mixture is stirred at room temperatureovernight. The mixture is concentrated, the residue is triturated withacetonitrile and the solid is filtered off and dried under high vacuum.This gives 230 mg (24% of theory) of the target compound.

LC-MS (Method 4): R_(t)=0.79 min; MS (ESIpos): m/z=342 [M+H]⁺.

Example 15A2-Amino-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile

500 mg (4.094 mmol) of 4-hydroxybenzaldehyde and 554 mg (8.393 mmol) ofmalononitrile are initially charged in 5 ml of methanol, and 4.42 g(24.565 mmol) of sodium methoxide, 30% strength in methanol, are added.The mixture is then stirred at room temperature for 2 hours. Theprecipitated solid is filtered off, washed with methanol and dried underhigh vacuum. This gives 613 mg (76% of theory) of the target compound.

LC-MS (Method 3): R_(t)=1.33 min; MS (ESIpos): m/z=267 [M+H]⁺.

Example 16A2-Chloro-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile

7.98 g (15.285 mmol) of2-amino-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile areinitially charged in 120 ml of acetonitrile, 6.175 ml (45.855 mmol) ofisoamyl nitrite and 6.165 g (45.855 mmol) of copper(II) chloride areadded and the mixture is stirred at room temperature overnight. 1Nhydrochloric acid is added, and the reaction mixture is extracted withethyl acetate. The organic phase is washed with saturated aqueous sodiumbicarbonate solution and with water, dried over sodium sulphate andconcentrated. The residue is purified on a silica gel column (mobilephase: toluene/ethyl acetate 2:1). This gives 1.3 g (23% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=10.29 (s, 1H), 7.49 (d, 2H), 6.98 (d, 2H),4.12 (s, 3H).

LC-MS (Method 1): R_(t)=2.04 min; MS (ESIpos): m/z=286 [M+H]⁺.

Example 17A4-(4-Hydroxyphenyl)-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile

1.3 g (4.550 mmol) of2-chloro-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile areinitially charged in 10 ml of DMF, 426 mg (5.460 mmol) of sodiumsulphide are added and the mixture is stirred at room temperatureovernight. The reaction mixture is reacted further without any furtherpurification.

LC-MS (Method 4): R_(t)=0.74 min; MS (ESIpos): m/z=284 [M+H]⁺.

Example 18A 4-(Chloromethyl)-N-(4-fluorophenyl)-1,3-thiazole-2-amine

Method A: Over a period of 1.5 h, a warm solution of 160 g (1.26 mol) of1,3-dichloroacetone in 480 ml of acetone is metered into a suspensionvon 202 g (1.19 mol) of 4-fluorophenylthiourea in 660 ml of acetone, andthe mixture is stirred at 40° C. for 4.5 h and at RT overnight. Thecrystals are filtered off with suction, washed with acetone and driedunder reduced pressure at 50° C.

Yield: 328 g of colourless crystals (93% of theory)

According to NMR, the product obtained consists to about 22% of thedesired title compound in a mixture with about 78% of the non-dehydratedintermediate4-(chloromethyl)-2-[(4-fluorophenyl)amino]-4,5-dihydro-1,3-thiazol-4-ol.This product is further used as such, without further separation.

Method B: 600 mg (4.7 mmol) of 1,3-dichloroacetone and 768 mg (4.5 mmol)of 4-fluorophenylthiourea are dissolved in 10 ml of DMF and stirred at80° C. for 4 h. 200 ml of water are added, and the mixture is extractedthree times with ethyl acetate. The combined organic phases are washedwith water and saturated aqueous sodium chloride solution, dried oversodium sulphate and concentrated to give a dark oil. This residue ischromatographed on 150 g of silica gel using isohexane→isohexane/ethylacetate (10:1). The product is directly used further.

Yield: 714 mg (60% of theory)

LC-MS (Method 5): R_(t)=2.14 min; MS (ESIpos): m/z=243 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=10.28 (s, 1H); 7.69-7.62 (m, 2H); 7.20-7.12(m, 2H); 6.94 (s, 1H); 4.67 (s, 2H).

Example 19A 4-(Chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole

The preparation is carried out as described in WO 03/053441 for Example6.

Example 20A 4-(Chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole

1 g (6.43 mmol) of 4-chlorobenzamide is heated together with 816 mg of1,3-dichloroacetone (6.43 mmol) at 135° C. for 1 h. The mixture isallowed to cool to RT, 1 ml of conc. sulphuric acid is added and themixture is stirred for 5 min. The mixture is then poured onto ice, andthe precipitate is filtered off with suction (946 mg). This precipitateis purified on 100 g of silica gel by column chromatography using agradient of cyclohexane/ethyl acetate 20:1 to 5:1.

Yield: 532 mg (36% of theory)

LC-MS (Method 5): R_(t)=2.35 min; MS (ESIpos): m/z=228 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.31 (s, 1H), 8.0 (d, 2H), 7.62 (d, 2H),4.75 (s, 2H).

Example 21A 4-(Chloromethyl)-2-(3,4-difluorophenyl)-1,3-thiazole

3.3 g (26 mmol) of 1,3-dichloroacetone and 4.5 g mg (26 mmol) of3,4-difluorophenylthiourea are boiled in 45 ml of ethanol at refluxovernight. The solvent is evaporated under reduced pressure and theresidue is purified by two silica gel chromatographies(cyclohexane/ethyl acetate 4:1 and isohexane/ethyl acetate 10:1).

Yield: 1.94 g (30% of theory)

LC-MS (Method 8): R_(t)=3.26 min; MS (ESIpos): no ionization

¹H-NMR (400 MHz, DMSO-d₆): δ=8.03-7.94 (m, 1H), 7.88 (s, 1H), 7.84-7.80(m, 1H), 7.63-7.54 (m, 1H), 4.89 (s, 2H).

Example 22A 4-(Hydroxymethyl)-N-methylpyridine-2-carboxamide

The preparation is carried out as described in U.S. Pat. No. 6,689,883for intermediate H.

Example 23A 4-(Chloromethyl)-N-methylpyridine-2-carboxamidehydrochloride

10 g (45.32 mmol) of the compound from Example 22A are suspended in 160ml of dichloromethane and cooled to 0° C. After addition of 16.18 g(135.96 mmol) of thionyl chloride, the reaction mixture is warmed to RTand stirred at RT overnight. The mixture is then concentrated byevaporation and the residue is dried under high vacuum.

Yield: 10 g (quant.)

LC-MS (Method 4): R_(t)=0.71 min; MS (ESIpos): m/z=185 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=8.85-8.78 (m, 1H), 8.65 (d, 1H), 8.10 (s,1H), 7.64 (d, 1H), 4.90 (s, 2H), 2.83 (d, 3H).

Example 24A4-{[(6-Amino-3,5-dicyano-4-phenylpyridin-2-yl)sulphanyl]methyl}-N-methylpyridine-2-carboxamide

1 g (3.96 mmol) of2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile, 0.96 g (4.36mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochlorideand 1.33 g (15.84 mmol) of sodium bicarbonate are dissolved in 20 ml ofDMF and stirred at RT for 2 h. 500 ml of water are added to the reactionmixture. The precipiate is filtered off and washed with water.

Yield: 1.42 g (90% of theory)

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=401 [M+H]⁺.

¹H-NMR (400 MHz, DMSO-d₆): 6 (400 MHz)=8.74 (q, 1H), 8.55 (d, 1H),8.30-7.96 (s br, 2H), 8.15 (s, 1H), 7.80-7.75 (m, 1H), 7.58-7.50 (m,5H), 4.60 (s, 2H), 2.81 (d, 3H).

Example 25A4-{[(6-Chloro-3,5-dicyano-4-phenylpyridin-2-yl)thio]methyl}-N-methylpyridine-2-carboxamide

1.42 g (3.55 mmol) of the compound from Example 24A are initiallycharged in 30 ml of acetonitrile, 0.96 ml (7.10 mmol) of isopentylnitrite and 0.95 g (7.10 mmol) of copper(II) chloride are added and themixture is stirred at 60° C. for 5 hours. Once more, the same amount ofcopper(II) chloride is added and the mixture is stirred at 60° C.overnight. 7 ml of 1N hydrochloric acid are added, the mixture isextracted three times with ethyl acetate and the combined organic phasesare washed with saturated aqueous sodium chloride solution, dried oversodium sulphate and concentrated. The residue is purified by preparativeHPLC (with 0.1% TFA added).

Yield: 1.31 g (87% of theory)

LC-MS (Method 2): R_(t)=2.46 min; MS (ESIpos): m/z=420 [M+H]⁺.

Example 26A4-{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}benzenecarbaldehyde

2 g (16.38 mmol) of p-methoxybenzaldehyde together with 3.7 g (24.57mmol) of (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane and 15.8 g(114.64 mmol) of potassium carbonate are stirred in 10 ml of DMF at 130°C. overnight. The mixture is then added to water and extracted withmethylene chloride. The organic phase is washed with saturated aqueoussodium chloride solution, dried over sodium sulphate and concentrated.The residue is purified on a silica gel column (mobile phase:cyclohexane/ethyl acetate 5:1). This gives 2.42 g (61% of theory) of thetarget compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=9.87 (s, 1H), 7.87 (d, 2H), 7.15 (d, 2H),4.47-4.41 (m, 1H), 4.19-4.15 (m, 1H), 4.13-4.08 (m, 2H), 3.79-3.75 (m,1H), 1.36 (s, 3H), 1.31 (s, 3H).

LC-MS (Method 4): R_(t)=1.00 min; MS (ESIpos): m/z=237 [M+H]⁺.

Example 27A2-Amino-4-(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrile

1.2 g (5.08 mmol) of4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}benzenecarbaldehyde and688 mg (10.41 mmol) of malononitrile are initially charged in 10 ml ofmethanol, 1.65 g (30.47 mmol) of sodium methoxide (30% strength,dissolved in methanol) are added and the mixture is stirred at roomtemperature for 2 hours. The precipitated solid is filtered off, washedwith methanol and dried under high vacuum. This gives 451 mg (23% oftheory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.92 (s, 2H), 7.47 (d, 2H), 7.13 (d, 2H),4.47-4.41 (m, 1H), 4.14-4.05 (m, 3H), 3.96 (s, 3H), 3.80-3.75 (m, 1H),1.37 (s, 3H), 1.32 (s, 3H).

LC-MS (Method 2): R_(t)=2.19 min; MS (ESIpos): m/z=381 [M+H]⁺.

Example 28A2-Chloro-4-(4-{[(2S)-2,3-dihydroxypropyl]oxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrile

450 mg (1.18 mmol) of2-amino-4-(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}phenyl)-6-methoxypyridine-3,5-dicarbonitriletogether with 478 μl (3.55 mmol) of isoamyl nitrite and 477 mg (3.55mmol) of copper(II) chloride are stirred in 10 ml of acetonitrile at 65°C. for 4 hours. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 202 mg (44% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.59 (d, 2H), 7.18 (d, 2H), 4.13 (s, 3H),4.09 (d, 1H), 4.01-3.92 (m, 1H), 3.85-3.80 (m, 1H), 3.47 (d, 2H).

LC-MS (Method 4): R_(t)=1.02 min; MS (ESIneg): m/z=340 [M−H—H₂O]⁺.

Example 29A4-(4-{[(2S)-2,3-Dihydroxypropyl]oxy}phenyl)-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile

100 mg (0.278 mmol) of2-chloro-4-(4-{[(2S)-2,3-dihydroxypropyl]oxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrileare initially charged in 5 ml of DMF, 26 mg (0.334 mmol) of sodiumsulphide are added and the mixture is stirred at room temperature for 4hours. The reaction mixture is reacted further without any furtherpurification.

LC-MS (Method 4): R_(t)=0.69 min; MS (ESIpos): m/z=358 [M+H]⁺.

Example 30A [2-(4-Chlorophenyl)-1,3-oxazol-4-yl]methanol

6 g (26.307 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazolewere heated under reflux in 526 ml (52.613 mmol) of 0.1 N aqueous sodiumhydroxide solution for 3 h. The mixture was then cooled to roomtemperature, and the precipitated solid was filtered off, washed with0.1N aqueous sodium hydroxide solution and dried under high vacuum. Thisgave 4.79 g (85% of theory) of the target compound.

LC-MS (Method 4): R_(t)=0.94 min; MS (ESIpos): m/z=210 [M+H]⁺.

WORKING EXAMPLES Example 12-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenyl-6-propoxypyridine-3,5-dicarbonitrile

37 μl (0.501 mmol) of 1-propanol are initially charged in 2 ml of DMF,20 mg (0.184 mmol) of potassium tert-butoxide are added and the mixtureis stirred for 15 minutes, after which 100 mg (0.167 mmol) of2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile,dissolved in 2 ml of DMF, are added. The reaction mixture is stirred atroom temperature for one hour and then purified by preparative HPLC(acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 13 mg(15% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.95 (d, 2H), 7.74 (s, 1H), 7.62-7.57 (m,7H), 4.79 (s, 2H), 4.53 (t, 2H), 1.79-1.70 (m, 2H), 0.93 (t, 3H).

LC-MS (Method 1): R_(t)=3.07 min; MS (ESIpos): m/z=503 [M+H]⁺.

Example 22-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-6-(3-hydroxypropoxy)-4-phenylpyridine-3,5-dicarbonitrile

68 μl (0.939 mmol) of 1,3-propanediol are initially charged in 2 ml ofDMF, 38 mg (0.344 mmol) of potassium tert-butoxide are added and themixture is stirred for 15 minutes, after which 150 mg (0.313 mmol) of2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile,dissolved in 2 ml of DMF, are added. The reaction mixture is stirred atroom temperature for 1 hour and then purified by preparative HPLC(acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 98 mg(59% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.96 (d, 2H), 7.75 (s, 1H), 7.62-7.57 (m,7H), 4.78 (s, 2H), 4.68 (t, 2H), 3.55 (t, 2H), 1.94-1.87 (m, 2H).

LC-MS (Method 2): R_(t)=2.90 min; MS (ESIpos): m/z=519 [M+H]⁺.

Example 32-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(3-hydroxypropoxy)pyridine-3,5-dicarbonitrile

The preparation is carried out analogously to Example 2 from Example 4A.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.97 (d, 2H), 7.74 (s, 1H), 7.60-7.52 (m,4H), 7.15 (d, 2H), 4.91 (br s, 1H), 4.80 (s, 2H), 4.70-4.58 (m, 3H),4.09 (t, 2H), 3.74 (t, 2H), 3.54 (t, 2H), 1.90 (quintet, 2H).

LC-MS (Method 4): R_(t)=1.36 min; MS (ESIpos): m/z=579 [M+H]⁺.

Example 42-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(2-methylpropoxy)pyridine-3,5-dicarbonitrile

The preparation is carried out analogously to Example 2 from Example 4A.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.97 (d, 2H), 7.71 (s, 1H), 7.61-7.53 (m,4H), 7.15 (d, 2H), 4.92 (t, 1H), 4.79 (s, 2H), 4.30 (d, 2H), 4.09 (t,2H), 3.74 (q, 2H), 2.05 (septet, 1H), 0.91 (d, 6H).

LC-MS (Method 3): R_(t)=2.76 min; MS (ESIpos): m/z=577 [M+H]⁺.

Example 52-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-6-[(1-methylpyrrolidin-3-yl)oxy]-4-phenylpyridine-3,5-dicarbonitrile

25 μl (0.229 mmol) of 3-hydroxy-N-methylpyrrolidine are initiallycharged in 0.5 ml of THF, the mixture is cooled to 0° C., 249 μl (0.249mmol) of phosphazene base P(4)-t-Bu (1M in THF) are added and themixture is stirred at this temperature for 10 minutes. 120 mg (0.208mmol) of the compound from Example 3A are then added, and the mixture isstirred at RT overnight. The reaction mixture is then purified bypreparative HPLC (addition of 0.15% hydrochloric acid). This gives 38 mgof the impure target compound. This is dissolved in dichloromethane andwashed twice with 1N hydrochloric acid, once with water and once withsaturated aqueous sodium chloride solution. After drying over sodiumsulphate, the organic phase is concentrated on a rotary evaporator andthe crude product is purified once more by preparative HPLC (addition of0.15% hydrochloric acid).

Yield: 7 mg (6% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ=10.40 (br s, 1H), 7.98 (d, 2H), 7.80 (d,1H), 7.65-7.58 (m, 7H), 5.96-5.87 (m, 1H), 4.82 (s, 2H), 4.10-3.83 (m,1H), 3.78-3.68 (m, 1H), 3.58-3.42 (m, 1H), 3.30-3.09 (m, 1H), 2.89 (d,3H), 2.44-2.18 (m, 2H).

LC-MS (Method 2): R_(t)=2.00 min; MS (ESIpos): m/z=544 [M+H]⁺.

Example 62-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-6-(3-hydroxypropoxy)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile

30 μl (0.419 mmol) of 1,3-propanediol are initially charged in 2 ml ofDMF, 18 mg (0.154 mmol) of potassium tert-butoxide are added and themixture is stirred for 15 minutes, after which 75 mg (0.14 mmol) of2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile,dissolved in 2 ml of DMF, are added. The reaction mixture is stirred atroom temperature for 30 minutes and then purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 11 mg (15% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=9.45 (d, 1H), 8.38 (d, 1H), 7.95 (d, 2H),7.74 (s, 1H), 7.58 (d, 2H), 4.81 (s, 2H), 4.68 (t, 2H), 4.64 (t, 1H),3.53 (q, 2H), 1.93-1.87 (m, 2H).

LC-MS (Method 3): R_(t)=2.22 min; MS (ESIpos): m/z=526 [M+H]⁺.

Example 72-({[2-(4-Chlorophenyl)-1,3-oxazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

400 mg (1.222 mmol) of4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitriletogether with 306 mg (1.344 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 410 mg (4.888 mmol)of sodium bicarbonate in 8 ml of DMF are stirred at room temperatureovernight. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 10.4 mg (1.6% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.21 (s, 1H), 7.97 (d, 2H), 7.61 (d, 2H),7.54 (d, 2H), 7.14 (d, 2H), 4.87 (t, 1H), 4.63 (s, 2H), 4.21 (s, 3H),4.09 (t, 2H), 3.75 (m, 2H).

LC-MS (Method 4): R_(t)=1.39 min; MS (ESIpos): m/z=519 [M+H]⁺.

Example 82-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

2.095 g (6.399 mmol) of4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitriletogether with 1.875 g (7.679 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.613 g (19.197mmol) of sodium bicarbonate in 50 ml of DMF are stirred at roomtemperature overnight. Water and methanol are added, and the reactionmixture is placed in an ultrasonic bath for 2 minutes. A white solidprecipitates out and is filtered off, washed with methanol and driedunder high vacuum. The mother liquor is concentrated to half of theoriginal volume and placed in the fridge for 30 minutes. Theprecipitated solid is filtered off, washed with methanol and dried underhigh vacuum. The two precipitated solids are combined, giving a total of2.98 g (85% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.95 (d, 2H), 7.76 (s, 1H), 7.63-7.53 (m,4H), 7.15 (d, 2H), 4.93 (s br, 1H), 4.82 (s, 2H), 4.18 (s, 3H), 4.09 (t,2H), 3.75 (t br, 2H).

LC-MS (Method 3): R_(t)=2.45 min; MS (ESIpos): m/z=535 [M+H]⁺.

Example 93-[({3,5-Dicyano-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridin-2-yl}thio)methyl]benzoicacid

50 mg (0.153 mmol) of the compound from Example 10A together with 29 mg(0.168 mmol) of 3-(chloromethyl)benzoic acid and 38.5 mg (0.458 mmol) ofsodium bicarbonate are stirred in 0.6 ml of DMF at room temperature for2 h. Water is added and the reaction mixture is purified by preparativeHPLC (with 0.15% hydrochloric acid added).

Yield: 28 mg (39% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ=13.05 (s br, 1H), 8.11 (s, 1H), 7.84 (d,1H), 7.76 (d, 1H), 7.56 (d, 2H), 7.50 (t, 1H), 7.13 (d, 2H), 4.73 (s,2H), 4.18 (s, 3H), 4.09 (t, 2H), 3.80 (br s, 1H), 3.74 (t, 2H).

LC-MS (Method 9): R_(t)=3.28 min; MS (ESIpos): m/z=462 [M+H]⁺.

Example 103-{[(3,5-Dicyano-6-methoxy-4-phenylpyridin-2-yl)thio]methyl}benzoic acid

75 mg (0.177 mmol) of the compound from Example 11A together with 33 mg(0.194 mmol) of 3-(chloromethyl)benzoic acid and 44.5 mg (0.530 mmol) ofsodium bicarbonate are stirred in 1.0 ml of DMF at room temperatureovernight. Water is added and the reaction mixture is purified bypreparative HPLC (with 0.15% hydrochloric acid added).

Yield: 67 mg (94% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ=13.08 (s br, 1H), 8.12 (s, 1H), 7.86 (d,1H), 7.76 (d, 1H), 7.62-7.56 (m, 5H), 7.50 (t, 1H), 4.75 (s, 2H), 4.19(s, 3H).

LC-MS (Method 10): R_(t)=3.50 min; MS (ESIpos): m/z=402 [M+H]⁺.

Example 114-[4-(2-Hydroxyethoxy)phenyl]-2-methoxy-6-[(3-methoxybenzyl)sulphanyl]pyridine-3,5-dicarbonitrile

75 mg (0.229 mmol) of4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitriletogether with 36 μl (0.253 mmol) of 3-methoxybenzyl bromide and 52 mg(0.380 mmol) of potassium carbonate are stirred in 1 ml of DMF at roomtemperature overnight. The reaction mixture is purified by preparativeHPLC (acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). Thisgives 16 mg (56% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.56 (d, 2H), 7.28 (t, 1H), 7.15 (d, 2H),7.07-7.06 (m, 2H), 6.88 (m, 1H), 4.95 (t, 1H), 4.65 (s, 2H), 4.17 (s,3H), 4.10 (t, 2H), 3.75 (m, 2H).

LC-MS (Method 5): R_(t)=2.39 min; MS (ESIpos): m/z=448 [M+H]⁺.

Example 124-[4-(2-Hydroxyethoxy)phenyl]-2-methoxy-6-[(pyridin-3-ylmethyl)sulphanyl]pyridine-3,5-dicarbonitrile

494 mg (1.5 mmol) of2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrileare initially charged in 5 ml of DMF, 140 mg (1.8 mmol) of sodiumsulphide are added and the mixture is stirred at room temperature for 3hours. 311 mg (2.25 mmol) of potassium carbonate and 307 mg (1.8 mmol)of 3-picolyl chloride hydrochloride are then added. The reaction mixtureis stirred at 45° C. overnight and then purified by preparative HPLC(acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). Thisgives 255 mg (40% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.71 (s, 1H), 8.50 (d, 1H), 7.90 (d, 1H),7.54 (d, 2H), 7.40 (dd, 1H), 7.14 (d, 2H), 4.70 (s, 2H), 4.13 (s, 3H),4.10 (t, 2H), 3.75 (m, 2H).

LC-MS (Method 5): R_(t)=1.63 min; MS (ESIpos): m/z=419 [M+H]⁺.

Example 132-[({2-[(4-Fluorophenyl)amino]-1,3-thiazol-4-yl}methyl)sulphanyl]-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

122 mg (0.371 mmol) of4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrileare dissolved in 3 ml of DMF and 1 ml of ethanol, 118 mg (0.397 mmol) ofthe compound from Example 18A (Method A), 130 mg (0.94 mmol) ofpotassium carbonate and 20 mg (0.53 mmol) of sodium borohydride areadded and the mixture is stirred at 50° C. overnight. After addition of0.4 ml of 5N acetic acid, the product is purified by preparative HPLC(acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). Thisgives 59 mg (30% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=10.27 (s, 1H), 7.61-7.59 (m, 1H), 7.55 (d,2H), 7.15 (d, 2H), 7.12 (t, 2H), 6.86 (s, 1H), 4.93 (t, 1H), 4.61 (s,2H), 4.19 (s, 3H), 4.09 (t, 2H), 3.74 (q, 2H).

LC-MS (Method 5): R_(t)=2.42 min; MS (ESIpos): m/z=534 [M+H]⁺.

Example 142-({[2-(3,4-Difluorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

36 mg (0.111 mmol) of2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrileare initially charged in 1 ml of DMF, 34 mg (0.138 mmol) of4-(chloromethyl)-2-(3,4-difluorophenyl)-1,3-thiazole and 28 mg (0.332mmol) of sodium bicarbonate are added and the mixture is stirred at roomtemperature overnight. The reaction mixture is purified by preparativeHPLC (acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). Thisgives 33 mg (48% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.99-7.95 (m, 1H), 7.80-7.77 (m, 2H),7.61-7.57 (m, 1H), 7.15 (d, 2H), 4.93 (t, 1H), 4.81 (s, 2H), 4.18 (s,3H), 4.09 (t, 2H), 3.75 (q, 2H).

LC-MS (Method 11): R_(t)=2.80 min; MS (ESIpos): m/z=537 [M+H]⁺.

Example 152-({[2-(4-Chlorophenyl)-1,3-oxazol-4-yl]methyl}sulphanyl)-6-ethoxy-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitrile

100 mg (0.293 mmol) of2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitriletogether with 73 mg (0.322 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 98 mg (1.172 mmol)of sodium bicarbonate are stirred in 2 ml of DMF at room temperatureovernight. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 41.5 mg (26% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.23 (s, 1H), 7.96 (d, 2H), 7.62 (d, 2H),7.56 (d, 2H), 7.16 (d, 2H), 4.92 (s, 1H), 4.66 (m, 2H), 4.60 (s, 2H),4.09 (m, 2H), 3.75 (m, 2H), 1.38 (m, 3H).

LC-MS (Method 4): R_(t)=1.45 min; MS (ESIpos): m/z=533 [M+H]⁺.

Example 162-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-6-ethoxy-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitrile

100 mg (0.293 mmol) of2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitriletogether with 78 mg (0.322 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 98 mg (1.172 mmol)of sodium bicarbonate are stirred in 2 ml of DMF at room temperatureovernight. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5). This gives 77 mg (47% of theory) ofthe target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.95 (d, 2H), 7.74 (s, 1H), 7.58 (d, 2H),7.55 (d, 2H), 7.14 (d, 2H), 4.92 (t, 1H), 4.78 (s, 2H), 4.63 (q, 2H),4.09 (t, 2H), 3.75 (q, 2H), 1.34 (t, 3H).

LC-MS (Method 4): R_(t)=1.51 min; MS (ESIpos): m/z=549 [M+H]⁺.

Example 172-({[2-(4-Chlorophenyl)-1,3-oxazol-4-yl]methyl}sulphanyl)-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile

64 mg (0.224 mmol) of4-(4-hydroxyphenyl)-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitriletogether with 88 mg (0.269 mmol) of4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 57 mg (0.672 mmol)of sodium bicarbonate are stirred in 2 ml of DMF at room temperatureovernight. The reaction mixture is purified by preparative HPLC(acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 44 mg(41% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=10.2 (s, 1H), 8.23 (s, 1H), 7.97 (d, 2H),7.61 (d, 2H), 7.44 (d, 2H), 6.95 (d, 2H), 4.62 (s, 2H), 4.20 (s, 3H).

LC-MS (Method 4): R_(t)=1.43 min; MS (ESIpos): m/z=475 [M+H]⁺.

Example 184-({[3,5-Dicyano-6-(2-hydroxyethoxy)-4-phenylpyridin-2-yl]thio}methyl)-N-methylpyridine-2-carboxamide

22 mg (0.357 mmol) of 1,2-ethanediol are initially charged in 0.5 ml ofDMF, and 4.8 mg (0.179 mmol) of sodium hydride are added. After 15 minat RT, 50 mg (0.119 mmol) of the compound from Example 25A are added andthe reaction mixture is stirred at 115° C. overnight. After cooling, thereaction solution is purified by prep. HPLC.

Yield: 19 mg (28% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ=8.79 (q, 1H), 8.58 (d, 1H), 8.10 (d, 1H),7.70-7.58 (m, 6H), 4.69 (br s, 1H), 4.56 (t, 2H), 3.80 (t, 2H), 2.82 (d,3H).

LC-MS (Method 1): R_(t)=1.95 min; MS (ESIpos): m/z=446 [M+H]⁺.

The examples listed in Table 1 are prepared from the appropriatestarting materials analogously to Example 18 with subsequentpurification:

TABLE 1 LC-MS: R_(t) [min] (Method); Ex- MS (ESI): ample Structure m/zNo. (yield) [M +H]⁺ ¹H-NMR (DMSO-d₆): 19

2.12 min (Method 3); m/z = 565 δ (400 MHz) = 7.97 (d, 2H), 7.74 (s, 1H),7.59- 7.52 (m, 4H), 7.15 (d, 2H), 4.98 (t, 1H), 4.91 (t, 1H), 4.79 (s,2H), 4.63 (t, 2H), 4.09 (t, 2H), 3.78-3.70 (m, 4H). 20

3.17 min (Method 2); m/z = 575 δ (400 MHz) = 7.98 (d, 2H), 7.74 (s, 1H),7.61- 7.53 (m, 4H), 7.14 (d, 2H), 5.37 (quintet, 1H), 4.79 (s, 2H), 4.09(t, 2H), 3.73 (t, 2H), 2.44- 2.32 (m, 2H), 2.23-2.10 (m, 2H), 1.85-1.75(m, 1H), 1.68-1.53 (m, 1H).

Example 21 Formic acid4-[4-(2-hydroxyethoxy)phenyl]-2-[(1H-imidazol-4-ylmethyl)sulphanyl]-6-methoxypyridine-3,5-dicarbonitrile(1:1)

The compound is prepared analogously to the procedutre for Example 14from2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrileand 4-chloromethylimidazole.

Yield 3.8 mg (7% of theory)

¹H-NMR (500 MHz, DMSO-d₆): δ=8.12 (s, 1H) 7.61 (s, 1H), 7.54 (d, 2H),7.18-7.00 (m, 3H), 4.92 (t, 1H), 4.58 (s, 2H), 4.18 (s, 3H), 4.20 (s,3H) 4.10 (t, 2H), 3.73 (q, 2H).

LC-MS (Method 11): R_(t)=2.24 min; MS (ESIpos): m/z=408 [M+H]⁺.

Example 222-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-(4-{[(2S)-2,3-dihydroxypropyl]-oxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrile

The solution from Example 29A is stirred together with 75 mg (0.306mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 93 mg(1.112 mmol) of sodium bicarbonate at room temperature overnight. Thereaction mixture is purified by preparative HPLC (acetonitrile/water:10:90→95:5, with 0.1% TFA added). This gives 33 mg (20% of theory overtwo steps) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=7.95 (d, 2H), 7.76 (s, 1H), 7.57 (dd, 4H),7.14 (d, 2H), 5.05 (d, 1H), 4.82 (s, 2H), 4.70 (t, 1H), 4.18 (s, 3H),4.12-4.08 (m, 1H), 4.00-3.95 (m, 1H), 3.85-3.79 (m, 1H), 3.46 (t, 2H).

LC-MS (Method 4): R_(t)=1.41 min; MS (ESIpos): m/z=565 [M+H]⁺.

Example 232-{[2-(4-Chlorophenyl)-1,3-oxazol-4-yl]methoxy}-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile

190 mg (0.910 mmol) of [2-(4-chlorophenyl)-1,3-oxazol-4-yl]methanol areinitially charged in 2 ml of DMF, 37 mg (0.334 mmol) of potassium2-methylpropan-2-oxide are added and the mixture is stirred at roomtemperature for 20 min. 100 mg (0.303 mmol) of2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile,dissolved in 1 ml of DMF, are then added. The mixture is stirred at roomtemperature overnight, and the product is then isolated by preparativeHPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives31 mg (20% of theory) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆): δ=8.44 (s, 1H), 8.01 (d, 2H), 7.63 (d, 2H),7.54 (d, 2H), 7.15 (d, 2H), 5.62 (s, 2H), 4.19 (s, 3H), 4.09 (t, 2H),3.75 (t, 2H).

LC-MS (Method 3): R_(t)=2.23 min; MS (ESIpos): m/z=503 [M+H]⁺.

B. ASSESSING THE PHARMACOLOGICAL AND PHYSIOLOGICAL ACTIVITY

The pharmacological and physiological activity of the compoundsaccording to the invention can be demonstrated in the following assays:

B-1. Indirect Determination of the Adenosine Agonism by Way of GeneExpression

Cells of the CHO (Chinese Hamster Ovary) permanent line are transfectedstably with the cDNA for the adenosine receptor subtypes A1, A2a andA2b. The adenosine A1 receptors are coupled to the adenylate cyclase byway of G_(i) proteins, while the adenosine A2a and A2b receptors arecoupled by way of G_(s) proteins. In correspondence with this, theformation of cAMP in the cell is inhibited or stimulated, respectively.After that, expression of the luciferase is modulated by way of acAMP-dependent promoter. The luciferase test is optimized, with the aimof high sensitivity and reproducibility, low variance and goodsuitability for implementation on a robot system, by varying severaltest parameters, such as cell density, duration of the growth phase andthe test incubation, forskolin concentration and medium composition. Thefollowing test protocol is used for pharmacologically characterizingcells and for the robot-assisted substance screening:

The stock cultures are grown, at 37° C. and under 5% CO₂, in DMEM/F12medium containing 10% FCS (fetal calf serum) and in each case split 1:10after 2-3 days. Test cultures are seeded in 384-well plates with 2000cells per well and grown at 37° C. for approx. 48 hours. The medium isthen replaced with a physiological sodium chloride solution (130 mMsodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 20 mMHEPES, 1 mM magnesium chloride hexahydrate, 5 mM sodium bicarbonate, pH7.4). The substances to be tested, which are dissolved in DMSO, arepipetted into the test cultures (maximum final concentration of DMSO inthe test mixture: 0.5%) in a dilution series of from 5×10⁻¹¹ M to3×10⁻⁶M (final concentration). 10 minutes later, forskolin is added tothe A1 cells and all the cultures are subsequently incubated at 37° C.for four hours. After that, 35 ml of a solution which is composed of 50%lysis reagent (30 mM disodium hydrogenphosphate, 10% glycerol, 3%TritonX100, 25 mM TrisHCl, 2 mM dithiotreitol (DTT), pH 7.8) and 50%luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mMcoenzyme A, 10 mM tricine, 1.35 mM magnesium sulphate, 15 mM DTT, pH7.8) are added to the test cultures, which are shaken for approx. 1minute and the luciferase activity is measured using a camera system.The EC₅₀ values are determined, i.e., the concentrations at which 50% ofthe luciferase response is inhibited in the case of the A1 cell, and,respectively, 50% of the maximum stimulation with the correspondingsubstance is achieved in the case of the A2b and A2a cells. Theadenosine-analogous compound NECA (5-N-ethylcarboxamidoadenosine), whichbinds to all adenosine receptor subtypes with high affinity andpossesses an agonistic effect, is used in these experiments as thereference compound [Klotz, K. N., Hessling, J., Hegler, J., Owman, C.,Kull, B., Fredholm, B. B., Lohse, M. J., “Comparative pharmacology ofhuman adenosine receptor subtypes—characterization of stably transfectedreceptors in CHO cells”, Naunyn Schmiedebergs Arch. Pharmacol., 357, 1-9(1998)).

Table 1 below lists the EC₅₀ values of representative working examplesfor the receptor stimulation on adenosine A1, A2a and A2b receptorsubtypes:

TABLE 6 Example EC50 A1 [nM] EC50 A2a EC50 A2b No. (1 μM forskolin) [nM][nM] 1 1.3 3000 3000 2 0.7 3000 534 3 0.6 689 263 6 5.7 3000 3000 8 0.31220 105 11 0.8 1110 3000 12 1.2 547 3000 15 4.8 3000 3000 16 0.8 5273000 18 0.3 1740 3000 19 0.5 685 177 21 73.2 3000 28.6 22 2.1 1260 142

B-2. Studies on Isolated Blood Vessels

The caudal artery of anesthetized rats is excised and mounted in aconventional apparatus for measuring isolated blood vessels. The vesselsare perfused in a heated bath and contracted using phenylephrine. Theextent of the contraction is determined using a contraction meter. Testsubstances are added to the precontracted blood vessels, and thedecrease in the contraction of the vessels is measured. A decrease incontraction corresponds to dilation of the vessels. The concentration atwhich the contraction of the blood vessels is reduced by 50% is given asthe EC_(so) value of a test substance with respect to its relaxingproperties.

B-3. Measurement of Blood Pressure and Heart Rate on Awake Rats

Various dosages of test substances are administered orally to awake SHRrats (spontaneously hypertensive rats) carrying an internal transmittercapable of measuring permanently both blood pressure and heart rate(telemetric monitoring of hemodynamic parameters). Blood pressure, heartrate and their changes are then recorded over a period of 24 hours.

B-4. Measurement of Blood Pressure and Heart Rate on Awake Marmosets

Various concentrations of test substances are administered orally toawake marmosets which carry an internal transmitter capable of measuringpermanently both blood pressure and heart rate (telemetric monitoring ofhemodynamic parameters). Blood pressure, heart rate and their changesare then recorded over a period of 6-24 hours.

B-5. Indirect Determination of Adenosine Antagonism Via Gene Expression

Cells of the permanent line CHO K1 (Chinese Hamster Ovary) are stablytransfected with a reporter construct (CRE luciferase) and the cDNA forthe adenosine receptor subtype A2a or A2b. A2a or A2b receptors arecoupled via Gas proteins to the adenylate cyclase. Through receptoractivation, the adenylate cyclase is activated and therefore the cAMPlevel in the cell increases. Via the reporter construct, acAMP-dependent promoter, the change in the cAMP level is coupled toluciferase expression.

For determination of adenosine antagonism on the adenosine receptorsubtype A1, once again CHO K1 cells are stably transfected, but thistime with a Ca²⁺-sensitive reporter construct (NFAT-TA-Luc; Clontech)and an A1-Gα16 fusion construct. This receptor chimera is, in contrastto the native A1 receptor (Gαi-coupling), coupled to the phospholipaseC. The luciferase is expressed here as a function of the cytosolic Ca²⁺concentration.

The permanent cell lines are cultured in DMEM/F12 (Cat. No. BE04-687Q;BioWhittaker) with 10% FCS (fetal calf serum) and various additives (20ml/litre 1M HEPES (Cat. No. 15630; Gibco), 20 ml/litre GlutaMAX (Cat.No. 35050-038, Gibco), 14 ml/litre MEM sodium pyruvate (Cat. No.11360-039; Gibco) 10 ml/litre PenStrep (Cat. No. 15070-063; Gibco)) at37° C. under 5% carbon dioxide, and split twice weekly.

For testing in the 384-well plate format, the cells are sown at 2000cells/well in 25 μl/well sowing medium and cultured at 37° C. under 5%carbon dioxide until substance testing. The A2a and A2b cells are sown,24 h before substance testing, in medium with additives and 5% FCS, thebase medium used for the A2a cells being DMEM/F12 and the base mediumused for the A2b cells being OptiMEM (Cat. No. 31985-047; Gibco). TheA1-Gα16 cells are sown, 48 h before substance testing, in OptiMEM with2.5% dialysed FCS and additives. On the day of the test, prior to theaddition of the substance, the medium is replaced by 25 ml of Caftybuffer (Cat. No. T21-154; PAA) with 2 mM calcium chloride and 0.1% BSA(bovine serum albumin) Dilution series in Cafty buffer with 2 mM calciumchloride and 0.1% BSA (bovine serum albumin) and a suitable agonistconcentration are prepared from the substances to be tested, which aredissolved in DMSO. The substances are pipetted at a final concentrationof from 5×10⁻⁵ M to 2.56×10⁻¹¹ M to the test cultures, while the DMSOcontent on the cells should not exceed 0.5%. NECA (5-N-ethylcarboxamidoadenosine) at a final concentration of 30 nM, which roughlycorresponds to the EC₅₀ concentration, is used as agonist for the A2aand A2b cells. 25 nM CPA (N-6-cyclopentyladenosine), which roughlycorresponds to the EC₇₅ concentration, is used as agonist for theA1-Gα16 cells. After adding the substances, the cell plates areincubated for 3-4 h at 37° C. under 5% carbon dioxide. Then, 25 ml of asolution consisting to 50% of lysis reagent (30 nM disodium hydrogenphosphate, 10% glycerol, 3% Triton X-100, 25 mM TrisHCl, 2 mMdithiothreitol (DTT), pH 7.8) and to 50% of luciferase substratesolution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricin,1.35 mM magnesium sulphate, 15 mM DTT, pH 7.8) are added to the cellsdirectly before measurement. The luciferase activity is detected with aluminescence reader. The IC₅₀ values are determined, i.e. theconcentration at which the luciferase response, produced by therespective agonist, is inhibited to 50%. ZM241385, for the A2a and A2bcells, and DPCPX (1,3-dipropyl-8-cyclopentylxanthine), for the A1-Gα16cells, are used as reference antagonist.

B-6. Determination of Pharmacokinetic Parameters after Intravenous andOral Administration

The substance to be tested is administered intravenously as a solutionto animals (for example mice, rats, dogs), and oral administration takesplace as solution or suspension by gavage. After administration of thesubstance, blood is taken from the animals at fixed times and isheparinized, and then plasma is obtained therefrom by centrifugation.The substance is quantified analytically in the plasma by LC/MS-MS. Theplasma concentration/time courses found in this way are used tocalculate the pharmacokinetic parameters such as AUC (area under theconcentration-time curve), C_(max) (maximum plasma concentration),T_(1/2) (half-life) and CL (clearance) by means of a validatedpharmacokinetic computer program.

B-7. Determination of the Solubility Reagents Required:

-   -   PBS buffer pH 6.5: 90.00 g of NaCl p.a. (for example from Merck,        Art. No. 1.06404.1000), 13.61 g of KH₂PO₄ p.a. (for example from        Merck, Art. No. 1.04873.1000) and 83.35 g of 1 N aqueous sodium        hydroxide solution (for example from Bernd Kraft GmbH, Art. No.        01030.4000) are weighed into a 1 litre measuring flask, the        flask is filled with distilled water to 1 litre and the mixture        is stirred for 1 hour. Using 1 N hydrochloric acid (for example        from Merck, Art. No. 1.09057.1000) the pH is then adjusted to        6.5.    -   PEG/water solution (70:30 v/v): 70 ml of polyethylene glycol 400        (for example from Merck, Art. No. 8.17003.1000) and 30 ml of        distilled water are homogenized in a 100 ml measuring flask.    -   PEG/PBS buffer pH 6.5 (20:80 v/v): 20 ml of polyethylene glycol        400 (for example from Merck, Art. No. 8.17003.1000) and 80 ml of        PBS buffer pH 6.5 are homogenized in a 100 ml measuring flask.    -   Dimethyl sulphoxide (for example from Baker, Art. No. 7157.2500)    -   Distilled water.

Preparation of the Starting Solution (Original Solution):

At least 4 mg of the test substance are weighed accurately into awide-necked 10 mm screw V vial (from Glastechnik Gräfenroda GmbH, Art.No. 8004-WM-H/V15μ) with fitting screw cap and septum, in a pipettingrobot DMSO is added to a concentration of 50 mg/ml and the mixture isshaken for 10 minutes.

Preparation of the Calibration Solutions:

Preparation of the starting solution for calibration solutions (stocksolution): With the aid of a pipetting robot, 10 μl of the originalsolution are transferred into a microtiter plate and made up with DMSOto a concentration of 600 μg/ml. The sample is shaken until everythinghas gone into solution.

Calibration solution 1 (20 μg/ml): 1000 μl of DMSO are added to 34.4 μlof the stock solution, and the mixture is homogenized.

Calibration solution 2 (2.5 μg/ml): 700 μl of DMSO are added to 100 μlof calibration solution 1, and the mixture is homogenized.

Preparation of the Sample Solutions:

Sample solution for solubilities of up to 5 g/litre in PBS buffer pH6.5: 10 μl of the original solution are transferred into a microtiterplate, and 1000 μl of PBS buffer pH 6.5 are added.

Sample solution for solubilities of up to 5 g/litre in PEG/water(70:30): 10 μl of the original solution are transferred into amicrotiter plate, and 1000 μl of PEG/water (70:30) are added.

Sample solution for solubilities of up to 5 g/litre in PEG/PBS buffer pH6.5 (20:80): 10 μl of the original solution are transferred into amicrotiter plate, and 1000 μl of PEG/PBS buffer pH 6.5 (20:80) areadded.

Practice:

The sample solutions prepared in this manner are shaken at 1400 rpm in atemperature-adjustable shaker (for example Eppendorf Thermomixer comfortArt. No. 5355 000.011 with interchangeable block Art. No. 5362.000.019)at 20° C. for 24 hours. In each case 180 μl are taken from thesesolutions and transferred into Beckman Polyallomer Centrifuge Tubes(Art. No. 343621). These solutions are centrifuged at about 223 000×gfor one hour (for example Beckman Optima L-90K Ultracentrifuge with Type42.2 Ti Rotor at 42 000 rpm). From each of the sample solutions, 100 μlof the supernatant are removed and diluted 1:5 and 1:100 with DMSO. Fromeach dilution, a sample is transferred into a vessel suitable for HPLCanalysis.

Analysis:

The samples are analysed by RP-HPLC. Quantification is carried out usinga two-point calibration curve of the test compound in DMSO. Thesolubility is expressed in mg/litre. Analysis sequence: 1) calibrationsolution 2.5 mg/ml; 2) calibration solution 20 μg/ml; 3) sample solution1:5; 4) sample solution 1:100.

HPLC Method for Acids:

Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTSPAL, degasser (G1322A) and column thermostat (G1316A); column:Phenomenex Gemini C18, 50 mm×2 mm, 5μ; temperature: 40° C.; mobile phaseA: water/phosphoric acid pH 2; mobile phase B: acetonitrile; flow rate:0.7 ml/min; gradient: 0-0.5 min 85% A, 15% B; ramp: 0.5-3 min 10% A, 90%B; 3-3.5 min 10% A, 90% B; ramp: 3.5-4 min 85% A, 15% B; 4-5 min 85% A,15% B.

HPLC Method for Bases:

Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTSPAL, degasser (G1322A) and column thermostat (G1316A); column:VDSoptilab Kromasil 100 C18, 60 mm×2.1 mm, 3.5μ; temperature: 30° C.;mobile phase A: water+5 ml of perchloric acid/litre; mobile phase B:acetonitrile; flow rate: 0.75 ml/min; gradient: 0-0.5 min 98% A, 2% B;ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp: 6.5-6.7min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.

B-8. Determination of the Metabolic Stability

To determine the metabolic stability of test compounds, the latter areincubated in vitro with liver microsomes or, preferably, with primaryfresh hepatocytes of various animal species (for example from rat anddog) and also of human origin to obtain and to compare metaboliteprofiles of a hepatic phase I and phase II metabolism which is ascomplete as possible.

The test compounds are incubated at a concentration of 10-20 μM. To thisend, stock solutions of the substances at a concentration of 1-2 mM inacetonitrile are prepared and then pipetted at a dilution of 1:100 intothe incubation mixture. The liver microsomes are incubated at 37° C. in50 mM potassium phosphate buffer (pH 7.4) with and withoutNADPH-generating system consisting of 1 mM NADP⁺, 10 mM glucose6-phosphate and 1 unit of glucose 6-phosphate dehydrogenase. Primaryhepatocytes are also incubated at 37° C. in suspension in Williams Emedium. After an incubation time of 0-4 hours, the incubation mixturesare quenched with acetonitrile (final concentration about 30%) and theprotein is centrifuged off at about 15 000×g. The samples quenched inthis manner are either analyzed directly or stored at −20° C. untilanalysis.

Analysis is carried out using high-performance liquid chromatographywith ultraviolet and mass-spectrometric detection (HPLC-UV-MS/MS). Tothis end, the supernatants of the incubation samples are chromatographedusing suitable C18 reversed-phase columns and variable mobile phasemixtures of acetonitrile and 10 mM aqueous ammonium formate solution.The UV chromatograms in combination with mass-spectrometric MS/MS dataserve to identify the metabolites and to elucidate their structures.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted into pharmaceuticalpreparations in the following ways:

Tablet: Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and then mixed with the magnesium stearate for 5minutes. This mixture is compressed in a conventional tablet press (seeabove for format of the tablet). A guideline compressive force for thecompression is 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound of the inventionis added to the suspension. The water is added while stirring. Themixture is stirred for about 6 h until the swelling of the Rhodigel iscomplete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400.20 g of oral solution correspond to a singledose of 100 mg of the compound of the invention.

Production:

The compound of the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound of the invention has completelydissolved.

i.v. Solution:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically tolerated solvent (e.g.isotonic saline, 5% glucose solution and/or 30% PEG 400 solution). Thesolution is sterilized by filtration and used to fill sterile andpyrogen-free injection containers.

1. A compound of the formula (I)

in which X represents O or S, R¹ represents (C₆-C₁₀)-aryl or 5- to10-membered heteroaryl, where (C₆-C₁₀)-aryl and 5- to 10-memberedheteroaryl may be substituted by 1 or 2 substituents independently ofone another selected from the group consisting of halogen, nitro, cyano,(C₁-C₆)-alkyl, trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy, amino,mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino, hydroxycarbonyl,(C₁-C₆)-alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₆)-alkylaminocarbonyl,di-(C₁-C₆)-alkylaminocarbonyl, (C₃-C₇)-cycloalkylaminocarbonyl,aminosulphonyl, mono-(C₁-C₆)-alkylaminosulphonyl,di-(C₁-C₆)-alkylaminosulphonyl, (C₁-C₆)-alkylsulphonylamino,pyrrolidino, piperidino, morpholino, piperazino,N′—(C₁-C₄)-alkylpiperazino, pyrrolidinocarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazinocarbonyl,N′—(C₁-C₄)-alkylpiperazinocarbonyl and -L-R⁵, in which L represents abond, NH or O, R⁵ represents phenyl or 5- or 6-membered heteroaryl,where phenyl and 5- or 6-membered heteroaryl for their part may besubstituted by 1 to 3 substituents independently of one another selectedfrom the group consisting of halogen, nitro, cyano, (C₁-C₆)-alkyl,trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy, difluoromethoxy,trifluoromethoxy, amino, mono-(C₁-C₆)-alkylamino, di-(C₁-C₆)-alkylamino,hydroxycarbonyl and (C₁-C₆)-alkoxycarbonyl, R² represents hydrogen or(C₁-C₄)-alkyl, R³ represents phenyl or 5- or 6-membered heteroaryl,where phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to3 substituents independently of one another selected from the groupconsisting of halogen, cyano, hydroxyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₃-C₇)-cycloalkoxy, tetrahydrofuranyloxy, pyrrolidinyloxy and—NR^(A)R^(B), where (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy may be substitutedby 1 to 3 substituents independently of one another selected from thegroup consisting of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl,hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl,amino, aminocarbonyl, mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,and where (C₃-C₇)-cycloalkoxy, tetrahydrofuranyloxy and pyrrolidinyloxymay be substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of (C₁-C₄)-alkyl, hydroxyl, oxo and(C₁-C₄)-alkoxy, and in which R^(A) represents hydrogen or (C₁-C₆)-alkyl,where (C₁-C₆)-alkyl for its part may be substituted by 1 to 3 fluorinesubstituents, and where (C₁-C₆)-alkyl for its part may be substituted bya substituent selected from the group consisting of hydroxyl and(C₁-C₄)-alkoxy, R^(B) represents hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₁-C₆)-alkylcarbonyl, (C₁-C₄)-alkylsulphonyl or(C₃-C₇)-cycloalkylsulphonyl, where (C₁-C₆)-alkyl for its part may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, trifluoromethyl,(C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, amino, mono-(C₁-C₄)-alkylamino anddi-(C₁-C₄)-alkylamino, and where (C₃-C₇)-cycloalkyl for its part may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of (C₁-C₄)-alkyl, hydroxyl, oxo and(C₁-C₄)-alkoxy, or R^(A) and R^(B) together with the nitrogen atom towhich they are attached form a 4- to 7-membered heterocycle which maycontain a further ring heteroatom from the group consisting of N, O andS and may be substituted by 1 or 2 substituents independently of oneanother selected from the group consisting of (C₁-C₄)-alkyl, hydroxyl,oxo and (C₁-C₄)-alkoxy, or where two adjacent substituents at phenyltogether with the carbon atoms to which they are attached may form a1,3-dioxolane, 1,3-dioxane or 2,2-difluoro-1,3-dioxolane, R⁴ represents(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or 4- to 6-membered heterocyclyl,where (C₁-C₆)-alkyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₄)-alkoxy,hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, amino, mono-(C₁-C₄)-alkylamino,di-(C₁-C₄)-alkylamino, aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl and 5- or 6-membered heterocyclyl, where(C₁-C₄)-alkoxy may be substituted by 1 or 2 substituents independentlyof one another selected from the group consisting of hydroxyl and(C₁-C₄)-alkoxy and where 5- or 6-membered heterocyclyl may besubstituted by a substituent selected from the group consisting of oxoand (C₁-C₄)-alkyl and where (C₃-C₇)-cycloalkyl and 4- to 6-memberedheterocyclyl may be substituted by 1 or 2 substituents independently ofone another selected from the group consisting of (C₁-C₄)-alkyl,hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl,amino, mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, and N-oxides,salts, solvates, salts of the N-oxides and solvates of the N-oxides andsalts thereof.
 2. The compound according to claim 1 in which Xrepresents S, R¹ represents phenyl or 5- or 6-membered heteroaryl, wherephenyl and 5- or 6-membered heteroaryl may be substituted by 1 or 2substituents independently of one another selected from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,(C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,mono-(C₁-C₄)-alkylaminocarbonyl, di-(C₁-C₄)-alkylaminocarbonyl,(C₃-C₆)-cycloalkylaminocarbonyl, (C₁-C₄)-alkylsulphonylamino,morpholino, piperazino, N′-(C₁-C₄)-alkylpiperazino and -L-R⁵, in which Lrepresents a bond or NH, R⁵ represents phenyl or 5- or 6-memberedheteroaryl, where phenyl and 5- or 6-membered heteroaryl for their partmay be substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of fluorine, chlorine, cyano,(C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy, trifluoromethoxy, amino,hydroxycarbonyl and (C₁-C₄)-alkoxycarbonyl, R² represents hydrogen ormethyl, R³ represents phenyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,pyrazolyl, imidazolyl and pyridyl, where phenyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, pyrazolyl, imidazolyl and pyridyl may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of fluorine, (C₁-C₆)-alkyl, hydroxyl,(C₁-C₄)-alkoxy and —NR^(A)R^(B), where (C₁-C₆)-alkyl and (C₁-C₄)-alkoxymay be substituted by 1 to 3 substituents independently of one anotherselected from the group consisting of fluorine, trifluoromethyl,hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino, methylamino,ethylamino, N,N-dimethylamino and N,N-diethylamino, and in which R^(A)represents hydrogen or (C₁-C₄)-alkyl, where (C₁-C₄)-alkyl for its partmay be substituted by a substituent selected from the group consistingof hydroxyl and (C₁-C₄)-alkoxy, R^(B) represents hydrogen or(C₁-C₄)-alkyl, where (C₁-C₄)-alkyl for its part may be substituted by 1or 2 substituents independently of one another selected from the groupconsisting of hydroxyl, (C₁-C₄)-alkoxy and hydroxycarbonyl, R⁴represents (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or 5- or 6-memberedheterocyclyl, where (C₁-C₆)-alkyl may be substituted by 1 or 2substituents independently of one another selected from the groupconsisting of fluorine, trifluoromethyl, (C₃-C₇)-cycloalkyl, hydroxyl,methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,amino, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino and5- or 6-membered heterocyclyl, where 5- or 6-membered heterocyclyl forits part may be substituted by a substituent selected from the groupconsisting of oxo and methyl, and where (C₃-C₇)-cycloalkyl and 5- or6-membered heterocyclyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting ofmethyl, hydroxyl, methoxy, hydroxycarbonyl, methoxycarbonyl,ethoxycarbonyl, amino, methylamino and N,N-dimethylamino, and salts,solvates and solvates of the salts thereof.
 3. The compound according toclaim 1 in which X represents O or S, R¹ represents phenyl, thiazolyl,oxazolyl or pyridyl, where phenyl and pyridyl are substituted by 1 or 2substituents independently of one another selected from the groupconsisting of fluorine, chlorine, cyano, methyl, trifluoromethyl,methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,N,N-dimethylaminocarbonyl and N,N-diethylaminocarbonyl, and wherethiazolyl and oxazolyl are substituted by a -L-R⁵ substituent, in whichL represents a bond or NH, R⁵ represents phenyl, where phenyl for itspart may be substituted by 1 or 2 substituents independently of oneanother selected from the group consisting of fluorine, chlorine,methyl, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl andethoxycarbonyl, and where thiazolyl and oxazolyl may be substituted by asubstituent selected from the group consisting of fluorine, methyl,ethyl, methoxy, hydroxycarbonyl and methoxycarbonyl, R² representshydrogen or methyl, R³ represents phenyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, pyrazolyl, imidazolyl and pyridyl, where phenyl, pyrrolyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl and pyridyl maybe substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of fluorine, (C₁-C₆)-alkyl, hydroxyl,(C₁-C₄)-alkoxy and —NR^(A)R^(B), where (C₁-C₆)-alkyl and (C₁-C₄)-alkoxymay be substituted by 1 to 3 substituents independently of one anotherselected from the group consisting of fluorine, trifluoromethyl,hydroxyl, methoxy, ethoxy, hydroxycarbonyl, amino, methylamino,ethylamino, N,N-dimethylamino and N,N-diethylamino, and in which R^(A)represents hydrogen or (C₁-C₄)-alkyl, where (C₁-C₄)-alkyl for its partmay be substituted by a substituent selected from the group consistingof hydroxyl and (C₁-C₄)-alkoxy, R^(B) represents hydrogen or(C₁-C₄)-alkyl, where (C₁-C₄)-alkyl for its part may be substituted by 1or 2 substituents independently of one another selected from the groupconsisting of hydroxyl, (C₁-C₄)-alkoxy and hydroxycarbonyl, R⁴represents (C₁-C₆)-alkyl or (C₄-C₆)-cycloalkyl, where (C₁-C₆)-alkyl maybe substituted by 1 or 2 substituents independently of one anotherselected from the group consisting of fluorine, trifluoromethyl,(C₃-C₇)-cycloalkyl, hydroxyl, methoxy and ethoxy, and where(C₄-C₆)-cycloalkyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting ofmethyl, hydroxyl and methoxy, and salts, solvates and solvates of thesalts thereof.
 4. The compound according to claim 1 in which Xrepresents S, R¹ represents phenyl, thiazolyl, oxazolyl or pyridyl,where phenyl and pyridyl are substituted by 1 or 2 substituentsindependently of one another selected from the group consisting offluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy,hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,methylaminocarbonyl, ethylaminocarbonyl, N,N-dimethylaminocarbonyl andN,N-diethylaminocarbonyl, and where thiazolyl and oxazolyl aresubstituted by a -L-R⁵ substituent, in which L represents a bond or NH,R⁵ represents phenyl, where phenyl for its part may be substituted by 1or 2 substituents independently of one another selected from the groupconsisting of fluorine, chlorine, methyl, methoxy, ethoxy,hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl, and where thiazolyland oxazolyl may be substituted by a substituent selected from the groupconsisting of fluorine, methyl, ethyl, methoxy, hydroxycarbonyl andmethoxycarbonyl, R² represents hydrogen, R³ represents phenyl orthiazolyl, where phenyl may be substituted by 1 or 2 substituentsindependently of one another selected from the group consisting of(C₁-C₆)-alkyl, hydroxyl and (C₁-C₄)-alkoxy, where (C₁-C₆)-alkyl and(C₂-C₄)-alkoxy may be substituted by 1 or 2 substituents independentlyof one another selected from the group consisting of hydroxyl andmethoxy, and where thiazolyl may be substituted by a (C₁-C₆)-alkylsubstituent, where (C₁-C₆)-alkyl may be substituted by 1 or 2substituents independently of one another selected from the groupconsisting of hydroxyl and methoxy, R⁴ represents (C₁-C₄)-alkyl, wherealkyl may be substituted by 1 or 2 hydroxyl substituents, and salts,solvates and solvates of the salts thereof.
 5. A process for preparing acompound of the formula (I) as defined in claim 1, wherein [A] acompound of the formula (II-A)

in which X, R¹, R² and R³ each have the meanings given in claim 1, isconverted into a compound of the formula (III-A)

which is reacted in an inert solvent in the presence of a suitable basewith a compound of the formula (IV)R⁴—OH  (IV), in which R⁴ has the meaning given in claim 1, or [B] in thecase that X represents S, a compound of the formula (II-B)

in which R³ and R⁴ each have the meanings given in claim 1, is reactedin an inert solvent with an alkali metal sulphide to give a compound ofthe formula (III-B)

which is reacted in an inert solvent in the presence of a base with acompound of the formula (V)

in which R¹ and R² each have the meanings given in claim 1 and Qrepresents a suitable leaving group, and any protective groups presentare removed to provide the compound of the formula (I), which isoptionally converted with the appropriate (i) solvents and/or (ii) basesor acids into a solvate, salt and/or solvate of a salt.
 6. (canceled) 7.(canceled)
 8. (canceled)
 9. (canceled)
 10. A pharmaceutical compositioncomprising a compound according to claim 1 in combination with an inertnontoxic pharmaceutically suitable auxiliary.
 11. A pharmaceuticalcomposition comprising a compound according to claim 1 in combinationwith one or more further active ingredients selected from the groupconsisting of lipid metabolism-modifying active ingredients,antidiabetics, antihypertensive drugs and antithrombotic drugs.
 12. Apharmaceutical composition for the treatment and/or prophylaxis ofhypertension, coronary heart disease, acute coronary syndrome, anginapectoris, heart failure, myocardial infarction or atrial fibrillationcomprising a compound according to claim 1 in combination with an inertnontoxic pharmaceutically suitable auxiliary.
 13. A pharmaceuticalcomposition for the treatment and/or prophylaxis of diabetes, metabolicsyndrome or dyslipidemias comprising a compound according to claim 1 incombination with an inert nontoxic pharmaceutically suitable auxiliary.14. A method for the treatment and/or prophylaxis of hypertension,coronary heart disease, acute coronary syndrome, angina pectoris, heartfailure, myocardial infarction or atrial fibrillation comprisingadministering to a human or animal in need thereof an effective amountof at least one compound according to claim
 1. 15. A method for thetreatment and/or prophylaxis of diabetes, metabolic syndrome ordyslipidemias comprising administering to a human or animal in needthereof an effective amount of at least one compound according toclaim
 1. 16. The method of claim 5, wherein the compound of the formula(II-A) is converted into the compound of the formula (III-A) usingcopper(II) chloride and isoamyl nitrite in a suitable solvent.
 17. Themethod of claim 5, wherein Q represents halogen, mesylate, tosylate ortriflate.
 18. A method for the treatment and/or prophylaxis ofhypertension, coronary heart disease, acute coronary syndrome, anginapectoris, heart failure, myocardial infarction or atrial fibrillationcomprising administering to a human or animal in need thereof aneffective amount of the pharmaceutical composition according to claim10.
 19. A method for the treatment and/or prophylaxis of hypertension,coronary heart disease, acute coronary syndrome, angina pectoris, heartfailure, myocardial infarction or atrial fibrillation comprisingadministering to a human or animal in need thereof an effective amountof the pharmaceutical composition according to claim
 11. 20. A methodfor the treatment and/or prophylaxis of diabetes, metabolic syndrome ordyslipidemias comprising administering to a human or animal in needthereof an effective amount of the pharmaceutical composition accordingto claim
 10. 21. A method for the treatment and/or prophylaxis ofdiabetes, metabolic syndrome or dyslipidemias comprising administeringto a human or animal in need thereof an effective amount of thepharmaceutical composition according to claim 11.